TWI484961B - Diamine heterocyclic methyl ester compounds - Google Patents

Diamine heterocyclic methyl ester compounds Download PDF

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TWI484961B
TWI484961B TW099114522A TW99114522A TWI484961B TW I484961 B TWI484961 B TW I484961B TW 099114522 A TW099114522 A TW 099114522A TW 99114522 A TW99114522 A TW 99114522A TW I484961 B TWI484961 B TW I484961B
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amino
compound
phenyl
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pyrazine
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TW201105326A (en
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Itsuro Shimada
Kazuo Kurosawa
Takahiro Matsuya
Kazuhiko Iikubo
Yutaka Kondoh
Akio Kamikawa
Hiroshi Tomiyama
Yoshinori Iwai
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Astellas Pharma Inc
Kotobuki Pharmaceutical Co Ltd
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Description

二胺雜環甲醯胺化合物Diamine heterocarbazide compound

本發明係關於一種醫藥組成物，特別作為癌治療用醫藥組成物之有效成分為有用的二胺雜環甲醯胺化合物。The present invention relates to a pharmaceutical composition, particularly a diamine heterocyclic meglumine compound which is useful as an active ingredient of a pharmaceutical composition for cancer treatment.

肺癌為氣管、氣管支、肺胞的細胞失去正常功能之結果，係就由無秩序地增殖所造成者，因肺癌的死亡者數為全癌死亡的17%之最多，世界中一年間有約130萬人因肺癌而死亡。Lung cancer is the result of the loss of normal function of the cells of the trachea, trachea, and lung cells. It is caused by disorderly proliferation. The number of deaths due to lung cancer is 17% of the total cancer death, and about 130 in the world. Ten thousand people died of lung cancer.

對於肺癌之治療，大致分為手術(外科治療法)、抗癌劑(化療法)、放射線照射(放射線治療法)，但藉由該組織型該治療是否奏效會有變動。例如，肺癌之確定診斷為，藉由病理醫生的手以顯微鏡標本之細胞病理組織進行診斷，肺癌的20%程度之小細胞肺癌為一般惡性度較高，會急速增大並進展，多為轉移至其他臟器，故當表現時大多已經成為進行癌。因此，多數進行化療法或放射線治療法，相對於此等雖較具感受性但多會再發，且預後亦不佳。另一方面，剩下80%程度的非小細胞肺癌至某階段的手術療法被檢討，但該階段以後的手術適應並不佳，化療法或放射線治療法成為治療之主體。For the treatment of lung cancer, it is roughly classified into surgery (surgical treatment), anticancer (chemotherapy), and radiation (radiation therapy), but there is a change in whether or not the treatment is effective. For example, the diagnosis of lung cancer is diagnosed by the pathologist's hand using the cytopathological structure of the microscope specimen. The 20% lung cancer of lung cancer is generally malignant, and will rapidly increase and progress, mostly for metastasis. To other organs, most of them have become cancer when they are performed. Therefore, most of the chemotherapy or radiotherapy methods are relatively receptive, but the prognosis is not good. On the other hand, the surgical treatment of the remaining 80% of non-small cell lung cancer to a certain stage was reviewed, but the surgery after this stage was not well adapted, and chemotherapy or radiotherapy became the main body of treatment.

因此，對於任何肺癌，化療法係為該治療之重要選擇。Therefore, for any lung cancer, chemotherapy is an important choice for this treatment.

ALK(Anaplustic lymphoma kinase)為受體型酪胺酸激酶，於中央部具有細胞膜貫通區域，於該羧基末端側具有酪胺酸激酶區域，於胺基末端側具有細胞外區域之蛋白質。至今，對於神經芽細胞腫、神經膠芽腫、乳癌、黑色瘤(Melanoma)等幾項外胚葉作為起源的癌細胞，表現全長ALK已被報告(非專利文獻1)。又，對於人類惡性淋巴瘤的一部份病例，ALK基因經染色體轉位子的結果，與其他基因(例如NPM基因、CLTCL基因、TFG基因、TPM3基因、ATIC基因、及TPM4基因)融合，做出具有癌化能的融合型酪胺酸激酶已被報告(Science,vol.263，p.1281,1994；Blood,vol.86,p.1954,1995；Blood,vol.95,p.3204,2000；Blood,vol.94,p.3265,1999；Oncogene,vol.20,p.5623,2001)。對於發炎性筋線維芽細胞腫瘤(Inflammatory Myofibroblastic Tumor)，染色體轉位子的結果為CARS基因、SEC31L1基因、及RanBP2基因等其基因與ALK基因融合，作成融合型酪胺酸激酶(Laboratory Investigation,a journal of technical methods and pathology,vol.83,p.1255,2003；International Journal of Cancer,vol.118,p.1181,2006；Medicinal Research Reviews,vol.28,p.372,2008)。與ALK融合的多數同伴分子具有複合體形成區域，融合體本身亦被認為形成複合體，該複合體形成會引起無法控制ALK的酪胺酸激酶活性，細胞內訊號經異常活化結果，引起癌化(Cellular and Molecular Life Science,vol.61,p.2939,2004；Nature Reviews Cancer,vol.8,p.11,2008)。ALK (Anaplustic lymphoma kinase) is a receptor-type tyrosine kinase having a cell membrane-penetrating region in the central portion, a tyrosine kinase region on the carboxyl terminal side, and a protein in the extracellular region on the amine terminal side. Heretofore, a full-length ALK has been reported for cancer cells of various origins such as neuroblastic granuloma, glioma, breast cancer, and melanoma (Non-Patent Document 1). In addition, for a part of human malignant lymphoma, the ALK gene is fused to other genes (such as NPM gene, CLTCL gene, TFG gene, TPM3 gene, ATIC gene, and TPM4 gene) through fusion of chromosomes. Conjugated tyrosine kinases with cancerous properties have been reported (Science, vol. 263, p. 1281, 1994; Blood, vol. 86, p. 1954, 1995; Blood, vol. 95, p. 3204, 2000). ; Blood, vol. 94, p. 3265, 1999; Oncogene, vol. 20, p. 5623, 2001). For the Inflammatory Myofibroblastic Tumor, the results of the chromosomal transposon are the fusion of the CARS gene, the SEC31L1 gene, and the RanBP2 gene with the ALK gene to create a fusion tyrosine kinase (Laboratory Investigation, a journal) Of technical methods and pathology, vol. 83, p. 1255, 2003; International Journal of Cancer, vol. 118, p. 1181, 2006; Medicinal Research Reviews, vol. 28, p. 372, 2008). Most of the companion molecules fused to ALK have a complex-forming region, and the fusion itself is also considered to form a complex. The formation of the complex causes tyrosine kinase activity that cannot control ALK, and the intracellular signal is abnormally activated to cause canceration. (Cellular and Molecular Life Science, vol. 61, p. 2939, 2004; Nature Reviews Cancer, vol. 8, p. 11, 2008).

又，最近報告中揭示對於食道癌，TPM4-ALK融合蛋白的存在可藉由蛋白質體學解析方法得知(World Journal of Gastroenterology,vol.12,p.7104,2006；Journal of Molecular Medicine,vol.85,p.863,2007)。且，由肺癌患者的檢體可確認EML4(echinoderm microtubule associated protein like-4)與ALK之融合基因，該EML4-ALK融合基因具有腫瘤形成能，其為癌之原因基因，且該激酶活性之阻斷劑可抑制表現EML4-ALK融合蛋白質之各種細胞的增殖已被報告(專利文獻1、非專利文獻2)。且該文獻中記載EML4-ALK融合蛋白質的阻斷劑可作為EML4-ALK聚核苷酸陽性的肺癌患者之對肺癌的治療藥為有用。且，肺癌中存在EML4-ALK的多數變形體已被證明(專利文獻1、Annals of surgical oncology,vol.17,p.889,2010、Molecular Cancer Research,vol.7,p.1466,2009、Clinical Cancer Research,vo.15,p.3143,2009、Cancer,vol.115,p.1723,2009、Clinical Cancer Research,vol.14,p.6618,2008、Clinical Cancer Research,vol.14,p.4275,2008)，又TFG-ALK(Cell,vol.131,p.1190,2007)及KIF5B-ALK(Clinical Cancer Research,vol.15,p.3143,2009)的存在已被報告。且，已知EML4-ALK在肺癌，亦在大腸癌或乳癌的患者中表現的例子(Molecular Cancer Research,vol.7,p.1466,2009)。Furthermore, recent reports have revealed that for esophageal cancer, the presence of the TPM4-ALK fusion protein can be known by proteomic analytical methods (World Journal of Gastroenterology, vol. 12, p. 7104, 2006; Journal of Molecular Medicine, vol. 85, p. 863, 2007). Furthermore, the fusion gene of EML4 (echinoderm microtubule associated protein like-4) and ALK can be confirmed by the specimen of the lung cancer patient, and the EML4-ALK fusion gene has tumor formation ability, which is a causative gene of cancer, and the activity of the kinase is blocked. The release agent can suppress the proliferation of various cells expressing the EML4-ALK fusion protein (Patent Document 1 and Non-Patent Document 2). Further, a blocker of the EML4-ALK fusion protein described in the literature is useful as a therapeutic drug for lung cancer in a lung cancer patient with positive EML4-ALK polynucleotide. Moreover, most variants of EML4-ALK in lung cancer have been demonstrated (Patent Document 1, Annals of surgical oncology, vol. 17, p. 889, 2010, Molecular Cancer Research, vol. 7, p. 1466, 2009, Clinical). Cancer Research, vo. 15, p. 3143, 2009, Cancer, vol. 115, p. 1723, 2009, Clinical Cancer Research, vol. 14, p. 6618, 2008, Clinical Cancer Research, vol. 14, p. 4275 , 2008), and the existence of TFG-ALK (Cell, vol. 131, p. 1190, 2007) and KIF5B-ALK (Clinical Cancer Research, vol. 15, p. 3143, 2009) have been reported. Moreover, an example in which EML4-ALK is expressed in lung cancer, also in patients with colorectal cancer or breast cancer, is known (Molecular Cancer Research, vol. 7, p. 1466, 2009).

又，專利文獻1中揭示作為具有EML4-ALK融合蛋白質之阻斷活性的化合物，可舉出以下化合物A～D(所有化合物皆作為ALK阻斷劑的已知化合物)，該EML4-ALK融合蛋白質之阻斷活性值已具體地被揭示。然而，並未揭示本發明之二胺雜環甲醯胺化合物的具體內容。Further, Patent Document 1 discloses that as a compound having a blocking activity of an EML4-ALK fusion protein, the following compounds A to D (known compounds in which all compounds are ALK blocking agents), the EML4-ALK fusion protein are mentioned. The blocking activity value has been specifically revealed. However, the specific content of the diamine heterocyclic methylidene compound of the present invention is not disclosed.

各化學名為，化合物A為4-[(3’-溴-4’-羥基苯基)胺基]-6,7-二甲氧基喹唑啉(亦稱為WHI-P154)，化合物B為N-[2-(3-氯苯基)乙基]-2-[({[4-(三氟甲氧基)苯氧基]乙醯基}胺基)甲基]-1,3-唑-4-甲醯胺，化合物C為5-氯-N4 -[2-(異丙基磺醯基)苯基]-N2 -{2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}嘧啶-2,4-二胺(亦稱為TAE684)，化合物D為2-[(5-溴-2-{[2-甲氧基-4-(4-甲基哌嗪-1-基)苯基]胺基}嘧啶-4-基)胺基]-N-甲基苯磺胺。Each chemical name, compound A is 4-[(3'-bromo-4'-hydroxyphenyl)amino]-6,7-dimethoxyquinazoline (also known as WHI-P154), compound B Is N-[2-(3-chlorophenyl)ethyl]-2-[({[4-(trifluoromethoxy)phenoxy]ethenyl)amino)methyl]-1,3 - Zombia-4-carboxamide, compound C is 5-chloro-N 4 -[2-(isopropylsulfonyl)phenyl]-N 2 -{2-methoxy-4-[4-(4 -Methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine (also known as TAE684), compound D is 2-[(5-bromo-2-{[ 2-Methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)amino]-N-methylbenzenesulfonamide.

又，對於ALK融合體表現淋巴瘤細胞，具有ALK阻斷活性的化合物之WHI-P154(前述化合物A)可抑制細胞增殖、誘導細胞凋亡已被報告(非專利文獻3)。但，並未具體揭示本發明之二胺雜環甲醯胺化合物。Further, in the ALK fusion-expressing lymphoma cells, WHI-P154 (the aforementioned compound A) having a compound having an ALK blocking activity has been reported to inhibit cell proliferation and induce apoptosis (Non-Patent Document 3). However, the diamine heterocarbazide compound of the present invention is not specifically disclosed.

又，作為經NPM基因與ALK基因之融合基因的融合蛋白質之阻斷劑，已知有TAE684(前述化合物C)。Further, as a blocking agent for a fusion protein of a fusion gene of the NPM gene and the ALK gene, TAE684 (the aforementioned compound C) is known.

TAE684為夾在2個-NH基之中央環為氯取代嘧啶環，故與本發明化合物之化學結構相異。TAE684 is a chlorine-substituted pyrimidine ring sandwiched between two central groups of -NH groups, and thus is different from the chemical structure of the compound of the present invention.

又，TAE684藉由NPM-ALK融合蛋白質之阻斷活性，可阻斷未分化大細胞性淋巴瘤(ALCL)的進展已被報告(非專利文獻4)。另一方面，雖有記載含有TAE684之化合物具有接著斑激酶(FAK)的阻斷活性，該阻斷活性對於非小細胞肺癌、小細胞肺癌的預防及/或處置有用，但對於具體的肺癌之治療效果完全無記載(專利文獻2)。又，有關本發明之二胺雜環甲醯胺化合物的具體內容亦無揭示。Further, TAE684 has been reported to block the progression of undifferentiated large cell lymphoma (ALCL) by the blocking activity of the NPM-ALK fusion protein (Non-Patent Document 4). On the other hand, although the compound containing TAE684 has a blocking activity of plaque kinase (FAK), the blocking activity is useful for the prevention and/or treatment of non-small cell lung cancer and small cell lung cancer, but for specific lung cancer. The therapeutic effect is completely undescribed (Patent Document 2). Further, the specific contents of the diamine heterocarbazide compound of the present invention are not disclosed.

且，已有報告記載ELM4-ALK表現在非小細胞肺癌細胞(NCI-H2228)、TFG-ALK表現在非小細胞肺癌患者、TAE684阻斷非小細胞肺癌細胞(NCI-H2228)之增殖阻斷(專利文獻1、非專利文獻5、6)。Furthermore, it has been reported that ELM4-ALK is expressed in non-small cell lung cancer cells (NCI-H2228), TFG-ALK is expressed in non-small cell lung cancer patients, and TAE684 blocks non-small cell lung cancer cells (NCI-H2228). (Patent Document 1, Non-Patent Documents 5 and 6).

又，亦有報告記載下述化合物具有Syk阻斷活性，作為過敏性、發炎、免疫疾病、血栓或癌等、Syk相關疾病之預防或治療劑的有效成分為有用(專利文獻3)。In addition, it is reported that the following compounds have Syk blocking activity, and are useful as an active ingredient of a prophylactic or therapeutic agent for Syk-related diseases such as allergic, inflammatory, immune diseases, thrombosis, and cancer (Patent Document 3).

(式中符號可參考該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物的具體內容並無揭示。又，對於EML4-ALK融合蛋白質之激酶活性的阻斷活性亦無揭示且無記載，對於癌之治療效果亦無具體揭示。However, the specific content of the diamine heterocarbazide compound of the present invention is not disclosed. Further, the blocking activity of the kinase activity of the EML4-ALK fusion protein was not revealed and was not described, and the therapeutic effect of the cancer was not specifically disclosed.

又，已有報告記載下述化合物具有蛋白質激酶C阻斷活性，可作為糖尿病性併發病、缺血、發炎或癌等、蛋白質激酶C的相關疾病之預防或治療劑的有效成分為有用(專利文獻4)。In addition, it has been reported that the following compounds have protein kinase C blocking activity, and are useful as an active ingredient of a prophylactic or therapeutic agent for diseases related to protein kinase C such as diabetic onset, ischemia, inflammation, or cancer (patent) Document 4).

(式中符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，對於本發明之二胺雜環甲醯胺化合物並無具體揭示。又，對於EML4-ALK融合蛋白質的激酶活性之阻斷活性並無揭示或記載，對於癌之治療效果亦無具體揭示。However, the diamine heterocarbalamine compound of the present invention is not specifically disclosed. Further, the blocking activity of the kinase activity of the EML4-ALK fusion protein is not disclosed or described, and the therapeutic effect of the cancer is not specifically disclosed.

又，已有報告記載下述化合物具有EML4-ALK融合蛋白質及變異EGFR蛋白質的激酶活性之阻斷活性，可作為含有肺癌等的癌治療劑之有效成分為有用(專利文獻5)。In addition, it has been reported that the following compounds have a blocking activity of the kinase activity of the EML4-ALK fusion protein and the variant EGFR protein, and are useful as an active ingredient of a cancer therapeutic agent containing lung cancer or the like (Patent Document 5).

(式中的-X-表示可被取代的1,3,5-三嗪-2,4-二基或喹唑啉-2,4-二基。其他式中之符號可參考該公報)(-X- in the formula represents a 1,3,5-triazine-2,4-diyl or quinazoline-2,4-diyl which may be substituted. The symbols in the other formulae can be referred to the publication)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed.

又，已有報告記載下述化合物具有含有ALK之各種激酶的阻斷活性，對於細胞增殖性疾病之治療為有用(專利文獻6)。Further, it has been reported that the following compounds have a blocking activity of various kinases containing ALK, and are useful for the treatment of cell proliferative diseases (Patent Document 6).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed.

又，己有報告記載下述化合物具有ALK及/或c-Met之阻斷活性，於增殖性疾病之治療上為有用(專利文獻7)。Further, it has been reported that the following compounds have a blocking activity of ALK and/or c-Met, and are useful for the treatment of proliferative diseases (Patent Document 7).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed.

又，已有報告記載下述化合物具有含有ALK之各種激酶的阻斷活性，對於過剩增殖性疾病或血管新生疾病的治療上有用(專利文獻8)。In addition, it has been reported that the following compounds have a blocking activity of various kinases containing ALK, and are useful for the treatment of an excess proliferative disease or an angiogenic disease (Patent Document 8).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed.

又，已有報告記載下述化合物具有含有IGF-1R或ALK之各種激酶的阻斷活性，對於癌治療上有用(專利文獻9)。Further, it has been reported that the following compounds have a blocking activity of various kinases containing IGF-1R or ALK, and are useful for cancer treatment (Patent Document 9).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed.

又，已有報告記載下述化合物具有Syk阻斷活性，對於過敏性、自身免疫疾病、癌或骨髓性細胞增殖異常之治療上有用(專利文獻10)。Further, it has been reported that the following compounds have Syk blocking activity and are useful for the treatment of allergic, autoimmune diseases, cancer or myelogenous cell proliferation abnormalities (Patent Document 10).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。又，對於EML4-ALK融合蛋白質的激酶活性之阻斷活性亦無揭示且無記載，對於癌之治療效果亦無具體揭示。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed. Further, the blocking activity of the kinase activity of the EML4-ALK fusion protein was not revealed and was not described, and the therapeutic effect of the cancer was not specifically disclosed.

又，已有報告記載下述化合物具有Aurora-B激酶阻斷活性，對於癌、感染症、發炎或自身免疫疾病之治療上為有用(專利文獻11)。Further, it has been reported that the following compounds have Aurora-B kinase blocking activity and are useful for the treatment of cancer, infectious diseases, inflammation, or autoimmune diseases (Patent Document 11).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。又，對於EML4-ALK融合蛋白質之激酶活性的阻斷活性並無揭示且無記載。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed. Further, the blocking activity of the kinase activity of the EML4-ALK fusion protein is not disclosed and is not described.

又，已有報告記載下述化合物具有具有STAT6活化阻斷活性或Th2細胞分化抑制活性，對於呼吸器疾病、氣喘或慢性閉塞性肺疾病的治療上有用(專利文獻12)。Further, it has been reported that the following compounds have STAT6 activation blocking activity or Th2 cell differentiation inhibitory activity, and are useful for the treatment of respiratory diseases, asthma, or chronic obstructive pulmonary diseases (Patent Document 12).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。又對於EML4-ALK融合蛋白質的激酶活性之阻斷活性並無揭示且無記載，對於癌之治療效果亦無具體揭示。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed. Further, the blocking activity of the kinase activity of the EML4-ALK fusion protein is not disclosed and is not described, and the therapeutic effect of the cancer is not specifically disclosed.

又，已有報告記載下述化合物具有PKC阻斷活性，對於過敏性、發炎、糖尿病或癌等治療上有用(專利文獻13)。Further, it has been reported that the following compounds have PKC blocking activity and are useful for therapeutics such as allergies, inflammation, diabetes, and cancer (Patent Document 13).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。又，對於EML4-ALK融合蛋白質的激酶活性之阻斷活性並無揭示亦無記載，對於癌之治療效果亦無具體揭示。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed. Further, the blocking activity of the kinase activity of the EML4-ALK fusion protein is not disclosed or described, and the therapeutic effect of the cancer is not specifically disclosed.

又，已有報告揭示下述化合物具有PLK-1及PLK-3阻斷活性，對於癌、細胞增殖性疾病、病毒感染症、自身免疫疾病、神經變性疾病之治療上有用(專利文獻14)。Further, it has been reported that the following compounds have PLK-1 and PLK-3 blocking activities, and are useful for the treatment of cancer, cell proliferative diseases, viral infections, autoimmune diseases, and neurodegenerative diseases (Patent Document 14).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。又，對於EML4-ALK融合蛋白質的激酶活性之阻斷活性並無揭示亦無記載。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed. Further, the blocking activity of the kinase activity of the EML4-ALK fusion protein is not disclosed or described.

又，已有報告記載下述化合物具有HSP-90阻斷活性，對於細胞增殖性疾病、癌、發炎、關節炎或血管新生疾病之治療上有用(專利文獻15)。Further, it has been reported that the following compounds have HSP-90 blocking activity and are useful for the treatment of cell proliferative diseases, cancer, inflammation, arthritis or angiogenesis diseases (Patent Document 15).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。又，對於EML4-ALK融合蛋白質的激酶活性之阻斷活性並無揭示亦無記載。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed. Further, the blocking activity of the kinase activity of the EML4-ALK fusion protein is not disclosed or described.

又，已有報告記載下述化合物具有ALK、c-Met或Mps1激酶阻斷活性，對於過剩增殖性疾病、癌或血管新生疾病之治療上有用(專利文獻16)。Further, it has been reported that the following compounds have ALK, c-Met or Mps1 kinase blocking activity, and are useful for the treatment of excessive proliferative diseases, cancers or angiogenesis diseases (Patent Document 16).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed.

又，已有報告揭示下述化合物具有Syk或Jak阻斷活性，對於心臟疾病、發炎、自身免疫疾病或細胞增殖性疾病的治療上有用(專利文獻17)。Further, it has been reported that the following compounds have Syk or Jak blocking activity and are useful for the treatment of heart diseases, inflammation, autoimmune diseases or cell proliferative diseases (Patent Document 17).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。又，對於EML4-ALK融合蛋白質的激酶活性之阻斷活性並無揭示亦無記載。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed. Further, the blocking activity of the kinase activity of the EML4-ALK fusion protein is not disclosed or described.

又，已有報告記載下述化合物具有IKK阻斷活性，對於發炎、免疫異常、癌、神經病變疾病、老化所引起的疾病、心臟疾病或代謝異常的治療上有用(專利文獻18)。Further, it has been reported that the following compounds have IKK blocking activity and are useful for the treatment of inflammation, immune abnormalities, cancer, neuropathy diseases, diseases caused by aging, heart diseases or metabolic abnormalities (Patent Document 18).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。又，對於EML4-ALK融合蛋白質的激酶活性的阻斷活性並無揭示亦無記載。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed. Further, the blocking activity of the kinase activity of the EML4-ALK fusion protein is not disclosed or described.

又，已有報告記載下述化合物具有含有ALK之各種激酶的阻斷活性，對於細胞增殖性疾病或癌的治療上有用(專利文獻19)。Further, it has been reported that the following compounds have a blocking activity of various kinases containing ALK, and are useful for the treatment of cell proliferative diseases or cancer (Patent Document 19).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed.

又，已有報告記載下述化合物具有ALK、ROS、IGF-1R或InsR之激酶阻斷活性，對於細胞增殖性疾病的治療上有用(專利文獻20)。Further, it has been reported that the following compounds have kinase blocking activity of ALK, ROS, IGF-1R or InsR, and are useful for the treatment of cell proliferative diseases (Patent Document 20).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed.

又，已有報告記載下述化合物具有ALK、ROS、IGF-1R或InsR的激酶阻斷活性，對於細胞增殖性疾病的治療上有用(專利文獻21)。Further, it has been reported that the following compounds have kinase blocking activity of ALK, ROS, IGF-1R or InsR, and are useful for the treatment of cell proliferative diseases (Patent Document 21).

(式中的符號可參照該公報)(The symbol in the formula can refer to the bulletin)

然而，有關本發明之二胺雜環甲醯胺化合物並無具體揭示。However, the diamine heterocarbazide compound of the present invention is not specifically disclosed.

[先行技術文獻][Advanced technical literature]

[專利文獻][Patent Literature]

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[專利文獻13]國際公開第WO 2009/012421號手冊[Patent Document 13] International Publication No. WO 2009/012421 Manual

[專利文獻14]國際公開第WO 2009/040399號手冊[Patent Document 14] International Publication No. WO 2009/040399

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[專利文獻21]國際公開第WO 2009/126515號手冊[Patent Document 21] International Publication No. WO 2009/126515

[非專利文獻][Non-patent literature]

[非專利文獻1]International Journal of Cancer、100卷、49頁、2002年[Non-Patent Document 1] International Journal of Cancer, 100, 49, 2002

[非專利文獻2]Nature、448卷、2號、561頁、2007年[Non-Patent Document 2] Nature, 448, 2, 561, 2007

[非專利文獻3]Laboratory Investigation、85卷、1544頁、2005年[Non-Patent Document 3] Laboratory Investigation, Vol. 85, 1544, 2005

[非專利文獻4]Proceedings of the National Academy of Science、104卷、1號、270頁、2007年[Non-Patent Document 4] Proceedings of the National Academy of Science, Vol. 104, No. 1, 270 pages, 2007

[非專利文獻5]Cell、131卷、1190頁、2007年[Non-Patent Document 5] Cell, Vol. 131, 1190, 2007

[非專利文獻6]Proceedings of the National Academy of Science、104卷、50號、19936頁、2007年[Non-Patent Document 6] Proceedings of the National Academy of Science, Vol. 104, No. 50, 19936, 2007

本發明提供醫藥組成物、特別作為癌治療用醫藥組成物之有效成分為有用且作為醫藥組成物之有效成分可更安全地使用的化合物。The present invention provides a pharmaceutical composition, particularly a compound which is useful as an active ingredient of a pharmaceutical composition for cancer treatment, and which can be used safely as an active ingredient of a pharmaceutical composition.

本發明者們對於作為癌治療用醫藥組成物之有效成分為有用的化合物進行詳細檢討結果，表現本發明的二胺雜環甲醯胺化合物具有優良EML4-ALK融合蛋白質的激酶活性之阻斷活性，可有用地作為癌治療用醫藥組成物之有效成分使用而完成本發明。The inventors of the present invention conducted a detailed review of a compound which is useful as an active ingredient of a pharmaceutical composition for cancer treatment, and showed that the diammonium carbamide compound of the present invention has a blocking activity of a kinase activity of an excellent EML4-ALK fusion protein. The present invention can be usefully used as an active ingredient of a pharmaceutical composition for cancer treatment.

即，本發明係關於式(I)的化合物或其鹽、以及式(I)的化合物或其鹽、及含有賦形劑之醫藥組成物。That is, the present invention relates to a compound of the formula (I) or a salt thereof, a compound of the formula (I) or a salt thereof, and a pharmaceutical composition containing an excipient.

(式中符號表示以下意思；-X-：式(II)或式(III)之基。(The symbol in the formula represents the following meaning; -X-: the group of the formula (II) or the formula (III).

A：-H、鹵素、低級烷基、環烷基、或低級烯基。A: -H, halogen, lower alkyl, cycloalkyl, or lower alkenyl.

R1 ：R 1 :

(1)由選自G1 及G2 群的1個以上基所取代之苯基(但，-X-為式(II)之基，且A為-H時、或式(III)的基時，R1 為由選自G2 群的1個以上基所取代，且可由選自G1 及G2 群的1個以上基所取代的苯基)、(1) a phenyl group substituted with one or more groups selected from the group consisting of G 1 and G 2 (however, -X- is a group of the formula (II), and when A is -H or a group of the formula (III) when, R 1 by one or more groups selected from G 2 group is substituted, and may be selected from the group G 2. 1 and G 1 or more substituted phenyl groups),

(2)可由選自G3 群的1個以上基所取代的芳香族雜環、或(2) an aromatic heterocyclic ring which may be substituted with one or more groups selected from the G 3 group, or

(3)可由1個以上的RZA 所取代的二環式縮合環(但，除去可由1個以上RZA 所取代的萘基或苯並二側氧基)。(3) by one or more R ZA substituted bicyclic fused ring (but, by removing one or more R ZA substituted naphthyl or benzo-oxo-two).

G1 群：鹵素、R00 、-O-R00 、-NHSO2 -R00 、-SO2 NH2 、-SO2 NH-R00 、胺基、硝基、及氰基。Group G 1 : halogen, R 00 , -OR 00 , -NHSO 2 -R 00 , -SO 2 NH 2 , -SO 2 NH-R 00 , an amine group, a nitro group, and a cyano group.

R00 ：可由各1個以上的鹵素所取代的低級烷基或低級烯基。R 00 : a lower alkyl group or a lower alkenyl group which may be substituted by one or more halogen atoms.

G2 群：-SO2 -R00 、-SO2 N(R00 )2 、-CONH2 、-CONH-R00 、-CON(R00 )2 、-NHCO-R00 、-N(R00 )CO-R00 、-NH-R00 、-CONH-(CH2 )n -O-R00 、-O-(CH2 )n -N(R00 )2 、-O-(CH2 )n -O-R00 、-O-(由芳香族雜環所取代之苯基)、苯基、芳香族雜環、及-W-Y-Z、以及式(IV)的基。Group G 2 : -SO 2 -R 00 , -SO 2 N(R 00 ) 2 , -CONH 2 , -CONH-R 00 , -CON(R 00 ) 2 , -NHCO-R 00 , -N(R 00 )CO-R 00 , -NH-R 00 , -CONH-(CH 2 ) n -OR 00 , -O-(CH 2 ) n -N(R 00 ) 2 , -O-(CH 2 ) n -OR 00 , -O- (phenyl substituted by an aromatic heterocyclic ring), a phenyl group, an aromatic heterocyclic ring, and -WYZ, and a group of the formula (IV).

n：1至3的整數。n: an integer from 1 to 3.

L1 及L2 ：與各所結合的碳原子共同成為一體，形成L 1 and L 2 : together with each bonded carbon atom, forming

(1)可與苯基進行縮合之環烷基、或(1) a cycloalkyl group condensable with a phenyl group, or

(2)非芳香族雜環。(2) Non-aromatic heterocyclic rings.

L3 ：鍵、或伸甲基。L 3 : a bond, or a methyl group.

-W-：鍵、哌啶-1,4-二基、或哌嗪-1,4-二基。-W-: bond, piperidine-1,4-diyl, or piperazine-1,4-diyl.

-Y-：鍵、-CO-、-SO2 -、-O-(CH2 )m -、或-N(R00 )-(CH2 )m -。-Y-: a bond, -CO-, -SO 2 -, -O-(CH 2 ) m -, or -N(R 00 )-(CH 2 ) m -.

m：0至3的整數。m: an integer from 0 to 3.

Z：Z:

(1)RZ0 、或(1) R Z0 , or

(2)可由選自GA 群的1個以上基所取代的非芳香族雜環。(2) A non-aromatic heterocyclic ring which may be substituted with one or more groups selected from the group consisting of G A groups.

RZ0 ：可由1個以上R00 所取代的環烷基。R Z0 : a cycloalkyl group which may be substituted by one or more R 00 .

GA 群：可由選自OH及RZO 所成群的基所取代的R00 、鹵素、-SO2 -R00 、-CO-R00 、-COO-R00 、-N(R00 )2 、側氧基、及-OH。Group G A : R 00 , halogen, -SO 2 -R 00 , -CO-R 00 , -COO-R 00 , -N(R 00 ) 2 which may be substituted by a group selected from the group consisting of OH and R ZO , pendant oxy, and -OH.

G3 群：鹵素、R00 、-O-R00 、苯基、-O-苯基、及-W-Z。Group G 3 : halogen, R 00 , -OR 00 , phenyl, -O-phenyl, and -WZ.

RzA ：R00 、或-(CH2 )n -Z。R zA : R 00 or -(CH 2 ) n -Z.

R2 ：R 2 :

(1)可由選自G4 群的1個以上基所取代的環烷基(且該環烷基可與可由各1個以上-O-低級烷基所取代的苯基或吡唑基進行縮合)、(1) a cycloalkyl group which may be substituted with one or more groups selected from the group G 4 (and the cycloalkyl group may be condensed with a phenyl group or a pyrazolyl group which may be substituted by one or more -O-lower alkyl groups each) ),

(2)可由選自G4 群的1個以上基所取代的非芳香族雜環、(2) a non-aromatic heterocyclic ring which may be substituted by one or more groups selected from the G 4 group,

(3)可由選自除側氧基以外的G4 群之1個以上基所取代的苯基、(3) a phenyl group which may be substituted with one or more groups selected from the group consisting of G 4 groups other than the pendant oxy group,

(4)可由選自除側氧基以外的G4 群之1個以上基所取代的吡啶基、或(4) a pyridyl group which may be substituted with one or more groups selected from the group G 4 other than the pendant oxy group, or

(5)可由選自G5 群的1個以上基所取代的低級烷基(但，除去2-(二甲胺)乙基、2-(二甲胺)丙基、及2-(二甲胺)丁基以外)。(5) a lower alkyl group which may be substituted with one or more groups selected from the G 5 group (however, 2-(dimethylamine)ethyl, 2-(dimethylamine)propyl, and 2-(dimethyl) are removed. Amine) other than butyl).

G4 群：可由選自GB 群的基所取代的低級烷基、胺基、-N(低級烷基)2 、-NH-低級烷基、-NHCO-低級烷基、-NHCOO-低級烷基、-CONH2 、-CONH-RZB 、-O-低級烷基、-CO-低級烷基、-COO-低級烷基、-OH、-COOH、側氧基、-SO2 -低級烷基、RZB 、-CO-RZB 、環烷基、及-W-Z。Group G 4 : lower alkyl group, amine group, -N(lower alkyl) 2 , -NH-lower alkyl group, -NHCO-lower alkyl group, -NHCOO-lower alkyl group which may be substituted by a group selected from the group G B group Base, -CONH 2 , -CONH-R ZB , -O-lower alkyl, -CO-lower alkyl, -COO-lower alkyl, -OH, -COOH, pendant oxy, -SO 2 -lower alkyl , R ZB , -CO-R ZB , cycloalkyl, and -WZ.

GB 群：胺基、-OH、環烷基、及RZB 。Group G B : amine group, -OH, cycloalkyl group, and R ZB .

RZB ：可選自鹵素及-O-低級烷基所成群之基所取代的苯基。R ZB : a phenyl group which may be substituted with a group in which a halogen and a -O-lower alkyl group are grouped.

G5 群：Group G 5 :

(1)G4 群之基、(1) The basis of the G 4 group,

(2)可由選自G4 群的1個以上基所取代的環烷基、(2) a cycloalkyl group which may be substituted by one or more groups selected from the group G 4

(3)可由選自G4 群的1個以上基所取代的非芳香族雜環、(3) a non-aromatic heterocyclic ring which may be substituted by one or more groups selected from the G 4 group,

(4)可由選自除側氧基以外的G4 群之1個以上基所取代的苯基、及(4) a phenyl group which may be substituted with one or more groups selected from the group consisting of G 4 groups other than a side oxy group, and

(5)可由選自除側氧基以外得G4 群之1個以上基所取代的吡啶基。(5) A pyridyl group which is substituted with one or more groups selected from the group consisting of G 4 groups other than a side oxy group.

R3 ：-H或低級烷基。R 3 : -H or lower alkyl.

或、R2 及R3 可與各所結合之氮原子成為一體形成可由選自G4 群之基所取代的環狀胺基)Or, R 2 and R 3 may be integrated with each of the bonded nitrogen atoms to form a cyclic amine group which may be substituted by a group selected from the group G 4 )

且，對於-SO2 N(R00 )2 、- CON(R00 )2 、-N(R00 )CO-R00 、-O-(CH2 )n -N(R00 )2 、及-N(R00 )2 ，含於各基之二個R00 可為相同或相異。又，對於-N(低級烷基)2 ，二個低級烷基可為相同或相異。And, for -SO 2 N (R 00) 2 , - CON (R 00) 2, -N (R 00) CO-R 00, -O- (CH 2) n -N (R 00) 2, and - N(R 00 ) 2 , the two R 00 contained in each group may be the same or different. Also, for -N(lower alkyl) 2 , the two lower alkyl groups may be the same or different.

又，若無特別記載，本說明書中之化學式中的符號亦使用於其他化學式時，相同符號表示相同意思。Further, unless otherwise stated, the symbols in the chemical formulas in the present specification are also used in the other chemical formulas, and the same symbols indicate the same meanings.

又，本發明係關於含有式(I)的化合物或其鹽之EML4-ALK融合蛋白質的激酶活性之阻斷劑。Further, the present invention relates to a blocker for kinase activity of an EML4-ALK fusion protein comprising a compound of the formula (I) or a salt thereof.

又，本發明係關於含有式(I)的化合物或其鹽之癌治療用醫藥組成物。且，該醫藥組成物亦包含含有式(I)之化合物或其鹽的癌治療劑。Further, the present invention relates to a pharmaceutical composition for cancer treatment comprising a compound of the formula (I) or a salt thereof. Further, the pharmaceutical composition also includes a cancer therapeutic agent containing the compound of the formula (I) or a salt thereof.

又，本發明係關於欲製造癌治療用醫藥組成物時的式(I)之化合物或其鹽的使用、於癌的治療時的式(I)的化合物或其鹽的使用、以及由將式(I)的化合物或其鹽之有效量投與於患者所成之癌治療方法。Further, the present invention relates to the use of the compound of the formula (I) or a salt thereof when the pharmaceutical composition for cancer treatment is to be produced, the use of the compound of the formula (I) or a salt thereof in the treatment of cancer, and the use of the compound The effective amount of the compound of (I) or a salt thereof is administered to a cancer treatment method formed by the patient.

式(I)的化合物或其鹽具有EML4-ALK融合蛋白質之激酶活性的阻斷活性、以及EML4-ALK融合蛋白質依賴性細胞的增殖抑制活性，可作為癌之型態的肺癌、作為其他型態之非小細胞肺癌或小細胞肺癌、又作為其他型態之ALK融合聚核苷酸陽性的癌、進一步作為其他型態之ALK融合聚核苷酸陽性的肺癌、進一步作為其他型態之ALK融合聚核苷酸陽性的非小細胞肺癌、進一步作為其他型態之ALK融合蛋白質陽性的癌、進一步作為其他型態之ALK融合蛋白質陽性的肺癌、進一步作為其他型態之ALK融合蛋白質陽性的非小細胞肺癌、進一步作為其他型態之EML4-ALK融合聚核苷酸陽性的癌、進一步作為其他型態之EML4-ALK融合聚核苷酸陽性的肺癌、進一步作為其他型態之EML4-ALK融合聚核苷酸陽性的非小細胞肺癌、進一步作為其他型態之EML4-ALK融合蛋白質陽性的癌、進一步作為其他型態之EML4-ALK融合蛋白質陽性的肺癌、進一步作為其他型態之EML4-ALK融合蛋白質陽性的非小細胞肺癌等預防及/或治療用醫藥組成物的有效成分而使用。The compound of the formula (I) or a salt thereof has a blocking activity of the kinase activity of the EML4-ALK fusion protein, and a proliferation inhibitory activity of the EML4-ALK fusion protein-dependent cell, and can be used as a cancer type lung cancer, as another type Non-small cell lung cancer or small cell lung cancer, as another type of ALK fusion polynucleotide-positive cancer, further as another type of ALK fusion polynucleotide-positive lung cancer, further as another type of ALK fusion Polynucleotide-positive non-small cell lung cancer, cancer further positive for other types of ALK fusion protein, lung cancer further positive for other types of ALK fusion protein, further non-small as positive for other types of ALK fusion protein Cell lung cancer, further as another type of EML4-ALK fusion polynucleotide-positive cancer, further as another type of EML4-ALK fusion polynucleotide-positive lung cancer, further as another type of EML4-ALK fusion polymerization Nucleotide-positive non-small cell lung cancer, further as another type of EML4-ALK fusion protein-positive cancer, further as another type of EML4 The ALK fusion protein-positive lung cancer is further used as an active ingredient of a pharmaceutical composition for prevention and/or treatment such as non-small cell lung cancer positive for other types of EML4-ALK fusion protein.

實施發明之形態Form of implementing the invention

以下對本發明做詳細說明。The invention will be described in detail below.

本說明書中「鹵素」表示F、Cl、Br、I。In the present specification, "halogen" means F, Cl, Br, and I.

所謂「低級烷基」表示直鏈或分支狀之碳數1至6(以下簡稱為「C1-6 」)的烷基，例如甲基、乙基、n-丙基、異丙基、n-丁基、異丁基、sec-丁基、tert-丁基、n-戊基、n-己基等，作為另外型態之C1-4 烷基，進一步作為其他型態之甲基、乙基、異丙基。The "lower alkyl group" means a straight or branched alkyl group having 1 to 6 carbon atoms (hereinafter abbreviated as "C 1-6 "), such as methyl, ethyl, n-propyl, isopropyl, n. -butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc., as a further type of C 1-4 alkyl, further as other forms of methyl, B Base, isopropyl.

所謂「低級烯基」為C2-6 的直鏈或分支狀之至少具有1個雙鍵的烴鏈之1價基，例如乙烯基、丙烯基、異丙烯基、丁烯基、戊烯基、1-甲基乙烯基、1-甲基-2-丙烯基、1,3-丁二烯基、1,3-戊二烯基等。作為其他型態之異丙烯基。The "lower alkenyl group" is a linear or branched monovalent group of a hydrocarbon chain having at least one double bond of C 2-6 , such as a vinyl group, a propenyl group, an isopropenyl group, a butenyl group or a pentenyl group. , 1-methylvinyl, 1-methyl-2-propenyl, 1,3-butadienyl, 1,3-pentadienyl, and the like. As other types of isopropenyl.

所謂「環烷基」為可交聯之C3-10 的飽和烴環基，例如環丙基、環丁基、環戊基、環己基、環庚基、環辛基、聯環[2.2.1]庚基、聯環[3.1.1]庚基、金剛烷基等。又，部分具有不飽和鍵，亦含有環戊烯基、環己烯基、環辛二烯基、聯環[3.1.1]庚烯基等。The "cycloalkyl group" is a crosslinkable C 3-10 saturated hydrocarbon ring group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2. 1] heptyl, bicyclo [3.1.1] heptyl, adamantyl and the like. Further, a part has an unsaturated bond, and also contains a cyclopentenyl group, a cyclohexenyl group, a cyclooctadienyl group, a bicyclo[3.1.1]heptenyl group, and the like.

所謂「環狀胺基」為，具有至少1個氮原子，亦可進一步具有1個以上的選自氮、氧及硫所成群之相同或相異的雜原子之環員數3至8的單環式非芳香族環狀胺之1價基，具有至少1個氮原子為具有結合鍵之基。具體而言，例如為氮丙啶、四氫吖唉基、吡咯烷基、哌啶基、氮雜環庚烷基、azocanyl、哌嗪基、高哌嗪基、嗎啉基、氧氮雜環庚烷基、硫代嗎啉基、氮雜環庚烷基等。作為另外其他型態之5至6員環的單環式非芳香族環狀胺之1價基。進一步作為其他型態之吡咯烷基、哌啶基、哌嗪基、嗎啉基。且，這些環如2,5-二氮雜聯環[2.2.1]庚基、9-氮雜聯環[3.3.1]壬基等，亦可經交聯。又，如二氫吡咯基、二氫吡啶基、四氫吡啶基、四氫吡嗪基等，於環之一部份亦可具有不飽和鍵。The "cyclic amine group" has at least one nitrogen atom, and may further have one or more ring members having the same or different hetero atoms selected from the group consisting of nitrogen, oxygen, and sulfur, and having a ring number of 3 to 8. The monovalent group of the monocyclic non-aromatic cyclic amine has at least one nitrogen atom as a group having a bonding bond. Specifically, for example, aziridine, tetrahydroindenyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, piperazinyl, homopiperazinyl, morpholinyl, oxazacyclocycle Heptyl, thiomorpholinyl, azepanyl and the like. A monovalent group of a monocyclic non-aromatic cyclic amine of another 5 to 6 membered ring of another type. Further, as other types of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl. Further, these rings such as 2,5-diazabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]fluorenyl and the like may also be crosslinked. Further, for example, a dihydropyrrolyl group, a dihydropyridyl group, a tetrahydropyridyl group or a tetrahydropyrazinyl group may have an unsaturated bond in one part of the ring.

所謂「非芳香族雜環」為，具有1至4個選自氮、氧及硫所成之雜原子的環員數3至10之單環式非芳香族雜環之1價基，例如有氮丙啶、四氫吖唉基、吡咯烷基、哌啶基、氮雜環庚烷基、二氮雜環庚烷基、azocanyl、哌嗪基、高哌嗪基、嗎啉基、氧氮雜環庚烷基、硫代嗎啉基、氮雜環庚烷基、四氫吡喃基、四氫呋喃基、二噁烷基、二氧雜戊環基、四氫噻吩基、四氫噻喃基等。作為其他型態之5至6員環之單環式非芳香族雜環的1價基。且，這些環如2,5-二氮雜聯環[2.2.1]庚基、9-氮雜聯環[3.3.1]壬基等，亦可經交聯。又，如二氫吡咯基、二氫吡啶基、四氫吡啶基、四氫吡嗪基等，於環的一部份亦可具有不飽和鍵。The "non-aromatic heterocyclic ring" is a monovalent group of a monocyclic non-aromatic heterocyclic ring having from 3 to 10 ring members having from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, for example, Aziridine, tetrahydroindenyl, pyrrolidinyl, piperidinyl, azepanyl, diazepine, azocanyl, piperazinyl, homopiperazinyl, morpholinyl, oxygen nitrogen Heterocyclic heptyl, thiomorpholinyl, Azepanyl, tetrahydropyranyl, tetrahydrofuranyl, dioxoalkyl, dioxapentyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and the like. A monovalent group of a monocyclic non-aromatic heterocyclic ring of a 5- to 6-membered ring of another type. Further, these rings such as 2,5-diazabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]fluorenyl and the like may also be crosslinked. Further, for example, a dihydropyrrolyl group, a dihydropyridyl group, a tetrahydropyridyl group or a tetrahydropyrazinyl group may have an unsaturated bond in a part of the ring.

所謂「芳香族雜環」為具有1至4個選自氮、氧及硫所成群的雜原子之環員數5至10的單環式芳香族雜環之1價基，例如吡啶基、吡咯基、吡嗪基、嘧啶基、噠嗪基、咪唑基、吡唑基、噻唑基、噁唑基、噻吩基、呋喃基、1,2,4-噁二唑基等。作為其他型態之吡啶基、咪唑基、吡唑基。進一步作為其他型態之吡啶基。The "aromatic heterocyclic ring" is a monovalent group of a monocyclic aromatic heterocyclic ring having 5 to 10 ring members having from 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur, for example, a pyridyl group, Pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, thienyl, furyl, 1,2,4-oxadiazolyl, and the like. As other forms of pyridyl, imidazolyl, pyrazolyl. Further as a pyridyl group of other forms.

所謂「二環式縮合環」為，(a)具有彼等環之二個環中，一方環為具有1至3個選自氮、氧及硫所成群之雜原子的環員數5至7之單環式雜環，另一方環為苯環，環員數9至11的二環式縮合環之1價基(但，除苯並二側氧基以外)、(b)具有這些環之二個環中，一方環為C5-7 的環烷基，另一方的環為苯環，環員數9至11的二環式縮合環之1價基、或(c)薁基。作為其他型態，具有這些環之二個環中，一方的環為具有1至3個選自氮、氧及硫所成群之雜原子的環員數5至7之單環式雜環，另一方的環為苯環，環員數9至11的二環式縮合環之1價基(但，除苯並二側氧基以外)，例如有喹啉基、苯並噻唑基、苯並咪唑基、吲哚、吲唑基、苯並噻吩基、苯並呋喃基、四氫異喹啉基、2,3-二氫-1,4-苯並二嗪基、1,2,3-苯並噻二唑基、2,1,3-苯並噻二唑基、及3,4-二氫-1,4-苯並噁嗪基等。又，作為其他型態之薁基。且，一方的環為具有飽和碳原子之單環式雜環時，這些環如3-側氧基-3,4-二氫-1,4-苯並噁嗪基、1-側氧基-1,2,3,4-四氫異喹啉基等，可由側氧基所取代。The "bicyclic condensed ring" is one of (a) two rings having the same ring, and one ring is a ring member having 5 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen, and sulfur. a monocyclic heterocyclic ring of 7; the other ring is a benzene ring; a monovalent group of a bicyclic condensed ring having a ring number of 9 to 11 (except for a benzodioxy group); (b) having these rings Among the two rings, one ring is a C 5-7 cycloalkyl group, the other ring is a benzene ring, a ring member having a ring number of 9 to 11 of a monovalent condensed ring, or (c) a fluorenyl group. As another form, one of the two rings having these rings is a monocyclic heterocyclic ring having 5 to 7 ring members having 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur. The other ring is a benzene ring, a monovalent group of a bicyclic condensed ring having a ring number of 9 to 11 (except for the benzodienyloxy group), for example, a quinolyl group, a benzothiazolyl group, a benzo group. Imidazolyl, anthracene, carbazolyl, benzothienyl, benzofuranyl, tetrahydroisoquinolinyl, 2,3-dihydro-1,4-benzodiazinyl, 1,2,3- Benzothiadiazolyl, 2,1,3-benzothiadiazolyl, and 3,4-dihydro-1,4-benzoxazinyl and the like. Also, it is used as a base for other types. Further, when one ring is a monocyclic heterocyclic ring having a saturated carbon atom, these rings are, for example, a 3-oxo-3,4-dihydro-1,4-benzoxazinyl group, a 1-sided oxy group- 1,2,3,4-tetrahydroisoquinolinyl or the like may be substituted by a pendant oxy group.

所謂「ALK融合聚核苷酸」為，ALK基因與其他基因融合後表現具有癌化能的融合型酪胺酸激酶之融合型聚核苷酸，例如有EML4-ALK融合聚核苷酸、TFG-ALK融合聚核苷酸、KIF5-ALK融合聚核苷酸、NPM-ALK融合聚核苷酸、CLTCL-ALK融合聚核苷酸、TPM3-ALK融合聚核苷酸、TPM4-ALK融合聚核苷酸、ATIC-ALK融合聚核苷酸、CARS-ALK融合聚核苷酸、SEC31L1-ALK融合聚核苷酸、及RanBP2-ALK融合聚核苷酸等。The "ALK fusion polynucleotide" is a fusion type polynucleotide of a fusion type tyrosine kinase which expresses a cancerous ability after the ALK gene is fused with other genes, for example, an EML4-ALK fusion polynucleotide, TFG -ALK fusion polynucleotide, KIF5-ALK fusion polynucleotide, NPM-ALK fusion polynucleotide, CLTCL-ALK fusion polynucleotide, TPM3-ALK fusion polynucleotide, TPM4-ALK fusion polynucleus Glycosylate, ATIC-ALK fusion polynucleotide, CARS-ALK fusion polynucleotide, SEC31L1-ALK fusion polynucleotide, and RanBP2-ALK fusion polynucleotide.

所謂「ALK融合蛋白質」為，藉由ALK融合聚核苷酸之表現所作成之融合型酪胺酸激酶。The "ALK fusion protein" is a fusion type tyrosine kinase produced by the expression of an ALK fusion polynucleotide.

所謂「EML4-ALK融合聚核苷酸」為，融合ALK基因與EML4基因，表現具有癌化能之ALK融合蛋白質的融合型聚核苷酸，該變形體例如含有EML4-ALK融合聚核苷酸v1(由專利文獻1之配列號碼1所示鹼配列所成之聚核苷酸)、EML4-ALK融合聚核苷酸v2(由專利文獻1的配列號碼6所示鹼配列所成之聚核苷酸)、及EML4-ALK融合聚核苷酸v3(由專利文獻1的配列號碼129所示鹼配列所成之聚核苷酸)以外，亦含有各種變形體(Annals of surgical oncology,vo1.17,p.889,2010、Molecular Cancer Research,vol.7,p.1466,2009、Clinical Cancer Research,vo.15,p.3143,2009、Cancer,vol.115,p.1723,2009、Clinical Cancer Research,vol.14,p.6618,2008、Clinical Cancer Research，vol.14,p.4275,2008等)。The "EML4-ALK fusion polynucleotide" is a fusion-type polynucleotide which expresses an ALK fusion protein having a cancerous ability by fusion of an ALK gene and an EML4 gene, and the variant includes, for example, an EML4-ALK fusion polynucleotide. V1 (a polynucleotide formed by the base arrangement shown in the alignment number 1 of Patent Document 1) and EML4-ALK fusion polynucleotide v2 (a polynucleus formed by the alkali arrangement shown in the alignment number 6 of Patent Document 1) In addition to the Glyceride) and the EML4-ALK fusion polynucleotide v3 (a polynucleotide formed by the base arrangement shown in the collocation number 129 of Patent Document 1), it also contains various variants (Annals of surgical oncology, vo1. 17, p. 889, 2010, Molecular Cancer Research, vol. 7, p. 1466, 2009, Clinical Cancer Research, vo. 15, p. 3143, 2009, Cancer, vol. 115, p. 1723, 2009, Clinical Cancer Research, vol. 14, p. 6618, 2008, Clinical Cancer Research, vol. 14, p. 4275, 2008, etc.).

所謂「EML4-ALK融合蛋白質」為藉由EML4-ALK融合聚核苷酸之表現所製作的融合型酪胺酸激酶。The "EML4-ALK fusion protein" is a fusion type tyrosine kinase produced by the expression of an EML4-ALK fusion polynucleotide.

所謂式(I)中之-X-表示式(II)的基時之式(I)的化合物或其鹽係表示式(V)的化合物或其鹽。The compound of the formula (I) wherein the -X- represents the formula (II) in the formula (I) or a salt thereof represents a compound of the formula (V) or a salt thereof.

所謂式(I)中之-X-表示式(III)的基之時的式(I)的化合物或其鹽係表示式(VI)的化合物或其鹽。The compound of the formula (I) or the salt thereof when the -X- group in the formula (I) represents the group of the formula (III) represents a compound of the formula (VI) or a salt thereof.

所謂「可被取代的」表示具有1～5個無取代、或取代基者。且，由複數基所取代時，這些基各可相同或相異。The term "may be substituted" means having 1 to 5 unsubstituted or substituted groups. Moreover, when substituted by a complex group, these groups may be the same or different.

所謂「由...所取代」表示具有1～5個取代基。且，由複數基所取代時，這些基各可為相同或相異。The phrase "substituted by" means having 1 to 5 substituents. Moreover, when substituted by a complex group, these groups may be the same or different.

所謂「可由1個以上鹵素所取代的低級烷基」，例如可由1至7個相同或相異的鹵素所取代的低級烷基，作為其他型態之可由1至5個鹵素所取代的低級烷基。進一步作為其他型態之可由1至3個鹵素所取代的低級烷基。The "lower alkyl group which may be substituted by one or more halogens", for example, a lower alkyl group which may be substituted by 1 to 7 identical or different halogens, and other lower forms of a lower alkyl group which may be substituted by 1 to 5 halogens. base. Further as other types of lower alkyl groups which may be substituted by 1 to 3 halogens.

所謂「可由1個以上鹵素所取代的低級烯基」，例如可由1至3個鹵素所取代的低級烯基。The "lower alkenyl group which may be substituted by one or more halogens" may, for example, be a lower alkenyl group which may be substituted by 1 to 3 halogens.

式(I)的化合物或其鹽之型態如以下所示。The form of the compound of the formula (I) or a salt thereof is shown below.

(1)對於式(I)，(1-1)-X-為式(II)之基，A為鹵素或低級烷基之化合物，作為其他型態(1-2)-X-為式(II)之基，A為鹵素之化合物，進一步作為其他型態(1-3)-X-為式(II)之基，A為低級烷基之化合物，進一步作為其他型態(1-4)-X-為式(II)之基，A為氯、乙基或異丙基之化合物，進一步作為其他型態(1-5)-X-為式(II)之基，A為氯之化合物，進一步作為其他型態(1-6)-X-為式(II)之基，A為乙基或異丙基之化合物，進一步作為其他型態(1-7)-X-為式(II)之基，A為乙基之化合物，進一步作為其他型態(1-8)-X-為式(II)之基，A為異丙基之化合物、或彼等鹽。(1) For the formula (I), (1-1)-X- is a group of the formula (II), and A is a compound of a halogen or a lower alkyl group, and is a form of another type (1-2)-X- ( The base of II), A is a halogen compound, further as another type (1-3)-X- is a group of formula (II), A is a lower alkyl compound, and further as another type (1-4) -X- is a group of formula (II), A is a compound of chlorine, ethyl or isopropyl, further as another type (1-5)-X- is a group of formula (II), and A is a compound of chlorine Further, as another type (1-6)-X- is a group of the formula (II), A is an ethyl or isopropyl compound, and further as another type (1-7)-X- is a formula (II) And A is a compound of the ethyl group, and further, as another type (1-8)-X-, is a group of the formula (II), and A is an isopropyl group compound or a salt thereof.

(2)對於式(I)，(2-1)R1 由-W-Y-Z所取代，且可由選自鹵素、R00 、-O-R00 、-NHSO2 -R00 、-SO2 NH-R00 、氰基、-SO2 -R00 、-SO2 N(R00 )2 、-CONH-R00 、-CON(R00 )2 、-NHCO-R00 、N(R00 )CO-R00 、-O-(CH2 )n -O-R00 、及環烷基所成群之基所取代的苯基，R00 為可由1個以上鹵素所取代的低級烷基，-Y-為鍵，Z為可由選自GA 群的1個以上所取代的非芳香族雜環之化合物，作為其他型態、(2-2)R1 的第4位碳由-W-Y-Z所取代，且第3位碳由選自鹵素、R00 及-O-R00 所成群之基所取代的苯基，R00 為可由1個以上鹵素所取代的低級烷基，-Y-為鍵，Z為可由1個以上R00 所取代的非芳香族雜環之化合物，進一步作為其他型態之(2-3)R1 的第4位碳由選自4-(4-甲基哌嗪-1-基)哌啶-1-基、4-(1-甲基哌啶-4-基)哌嗪-1-基、4-甲基哌嗪-1-基及4-異丙基哌嗪-1-基所成群之基所取代，且第3位碳可由選自氟、甲基、三氟甲基及甲氧基所成群之基所取代的苯基之化合物，進一步作為其他型態之(2-4)R1 的第4位碳由4-(4-甲基哌嗪-1-基)哌啶-1-基所取代，且第3位碳可由選自甲基、三氟甲基及甲氧基所成群之基所取代的苯基之化合物，進一步作為其他型態之(2-5)R1 的第4位碳可由4-甲基哌嗪-1-基所取代，且第3位碳可由選自氟及甲氧基所成群之基所取代的苯基之化合物，進一步作為其他型態之(2-6)R1 為4-{4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基之化合物，進一步作為其他型態之(2-7)R1 為3-甲基-4-{4-(4-甲基哌嗪-1-基)哌啶-1-基}苯基之化合物，進一步作為其他型態之(2-8)R1 為4-{4-(4-甲基哌嗪-1-基)哌啶-1-基}-3-(三氟甲基)苯基之化合物，進一步作為其他型態之(2-9)R1 為3-甲氧基-4-{4-(4-甲基哌嗪-1-基)哌啶-1-基}苯基之化合物，進一步作為其他型態之(2-10)R1 為4-(4-甲基哌嗪-1-基)苯基之化合物，進一步作為其他型態之(2-11)R1 為3-氟-4-(4-甲基哌嗪-1-基)苯基之化合物，進一步作為其他型態之(2-12)R1 為3-甲氧基-4-(4-甲基哌嗪-1-基)苯基之化合物，進一步作為其他型態之(2-13)R1 為3-甲基-4-(4-(1-甲基哌啶-4-基)哌嗪-1-基}苯基之化合物，進一步作為其他型態之(2-14)R1 為4-(4-異丙基哌嗪-1-基)-3-甲基苯基之化合物，或彼等鹽。(2) For the formula (I), (2-1) R 1 is substituted by -WYZ, and may be selected from the group consisting of halogen, R 00 , -OR 00 , -NHSO 2 -R 00 , -SO 2 NH-R 00 , Cyano group, -SO 2 -R 00 , -SO 2 N(R 00 ) 2 , -CONH-R 00 , -CON(R 00 ) 2 , -NHCO-R 00 , N(R 00 )CO-R 00 , -O-(CH 2 ) n -OR 00 , and a phenyl group substituted with a group of a cycloalkyl group, R 00 is a lower alkyl group which may be substituted by one or more halogens, -Y- is a bond, and Z is A compound of one or more substituted non-aromatic heterocyclic rings selected from the group consisting of G A groups may be substituted as another type, and the fourth carbon of (2-2) R 1 may be substituted by -WYZ, and the third carbon is a phenyl group substituted with a group selected from the group consisting of halogen, R 00 and -OR 00 , R 00 is a lower alkyl group which may be substituted by one or more halogens, -Y- is a bond, and Z may be one or more R 00 The substituted non-aromatic heterocyclic compound is further used as the other form of (2-3) R 1 at the 4th carbon selected from 4-(4-methylpiperazin-1-yl)piperidine-1 a group of 4-(1-methylpiperidin-4-yl)piperazin-1-yl, 4-methylpiperazin-1-yl and 4-isopropylpiperazin-1-yl groups Substituted, and the third carbon can be selected from the group consisting of fluorine, methyl, trifluoromethyl and methoxy The groups of compounds substituted phenyl group, the patterns of an even further (2-4) R 4 carbons bit 1 from 4- (4-methylpiperazin-1-yl) piperidine -1 a compound in which a group is substituted, and a carbon at the 3rd position may be substituted by a group selected from a group consisting of a methyl group, a trifluoromethyl group, and a methoxy group, and further as another type (2-5) R 1 The 4th carbon may be substituted by a 4-methylpiperazin-1-yl group, and the 3rd carbon may be a compound of a phenyl group substituted with a group selected from the group consisting of fluorine and a methoxy group, and further used as another type. (2-6) R 1 is a compound of 4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl, further as another type (2-7)R 1 is a compound of 3-methyl-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl, further as another form (2-8) R 1 is a compound of 4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}-3-(trifluoromethyl)phenyl, further as another type of (2-9)R 1 is a compound of 3-methoxy-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl, further as another form of (2-10)R 1 a compound of 4-(4-methylpiperazin-1-yl)phenyl, further as a further form (2- 11) R 1 is a compound of 3-fluoro-4-(4-methylpiperazin-1-yl)phenyl, further as another form (2-12) R 1 is 3-methoxy-4- a compound of (4-methylpiperazin-1-yl)phenyl, further as another form of (2-13)R 1 is 3-methyl-4-(4-(1-methylpiperidine-4) a compound of -phenyl)piperazin-1-yl}phenyl, further as another form of (2-14)R 1 is 4-(4-isopropylpiperazin-1-yl)-3-methylbenzene a compound, or a salt thereof.

(3)對於式(I)，(3-1)R2 為(i)可由選自-N(低級烷基)2 、低級烷基、-COO-低級烷基、-OH、-COOH、-CONH-RZB 、及嗎啉基所成群的1個以上基所取代的環烷基、或(ii)可由選自低級烷基、-CO-低級烷基、側氧基、-CO-RZB 、及苯甲基所成群的1個以上基所取代的非芳香族雜環之化合物，作為其他型態，(3-2)R2 為可由選自-N(低級烷基)2 、低級烷基、-COO-低級烷基、-OH、-COOH、-CONH-RZB 、及嗎啉基所成群之1個以上基所取代的環烷基之化合物，進一步作為其他型態之(3-3)R2 可由選自低級烷基、-CO-低級烷基、側氧基、-CO-RZB 、及苯甲基所成群的1個以上基所取代的非芳香族雜環之化合物，進一步作為其他型態之(3-4)R2 為(i)可由選自-N(低級烷基)2 、低級烷基、-COO-低級烷基、-OH、-COOH、-CONH-RZB 、及嗎啉基所成群的1個以上基所取代的環己基、(ii)可由選自低級烷基、-CO-低級烷基、側氧基、-CO-RZB 、及苯甲基所成群的1個以上基所取代的哌啶基、或(iii)四氫吡喃基之化合物，進一步作為其他型態之(3-5)R2 為可由選自-N(低級烷基)2 、低級烷基、-COO-低級烷基、-OH、-COOH、-CONH-RZB 、及嗎啉基所成群之1個以上基所取代的環己基之化合物，進一步作為其他型態之(3-6)R2 為可由選自低級烷基、-CO-低級烷基、側氧基、-CO-RZB 、及苯甲基所成群的1個以上基所取代的哌啶基之化合物，進一步作為其他型態之(3-7)R2 為四氫吡喃基之化合物，進一步作為其他型態之(3-8)R2 為4-羥基環己基、4-羥基-4-甲基環己基、或四氫吡喃-4-基之化合物，進一步作為其他型態之(3-9)R2 為4-羥基環己基之化合物，進一步作為其他型態之(3-10)R2 為4-羥基-4-甲基環己基之化合物，進一步作為其他型態之(3-11)R2 為四氫吡喃-4-基之化合物，或彼等鹽。(3) For the formula (I), (3-1) R 2 is (i) may be selected from -N(lower alkyl) 2 , lower alkyl, -COO-lower alkyl, -OH, -COOH, - a cyclic alkyl group substituted with one or more groups of CONH-R ZB and a morpholinyl group, or (ii) may be selected from the group consisting of lower alkyl, -CO-lower alkyl, pendant oxy, -CO-R a compound of a non-aromatic heterocyclic ring substituted with one or more groups in which ZB and a benzyl group are substituted, and (3-2) R 2 may be selected from -N (lower alkyl group) 2 as another form. a compound of a lower alkyl group, a -COO-lower alkyl group, -OH, -COOH, -CONH-R ZB , and a cycloalkyl group substituted with one or more groups of a morpholinyl group, further as another type (3-3) R 2 may be a non-aromatic impurity substituted with one or more groups selected from the group consisting of a lower alkyl group, a -CO-lower alkyl group, a pendant oxy group, -CO-R ZB , and a benzyl group. a compound of the ring, further as another type of (3-4) R 2 is (i) may be selected from the group consisting of -N(lower alkyl) 2 , lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-R ZB, morpholinyl group and the groups of the above groups substituted with a cyclohexyl group, (ii) may be selected from lower alkyl, CO- lower alkyl group, an oxygen-side , -CO-R ZB, benzyl, and groups of one or more of the groups substituted piperidinyl group, or (iii) a compound of the tetrahydropyranyl group, the patterns for an even further (3-5) R 2 is one or more groups which may be grouped from -N(lower alkyl) 2 , lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-R ZB , and morpholinyl Substituted cyclohexyl compounds, further as other forms of (3-6) R 2 may be selected from the group consisting of lower alkyl, -CO-lower alkyl, pendant oxy, -CO-R ZB , and benzyl. a compound of a piperidinyl group substituted with one or more groups, further as a compound of the other type (3-7) R 2 is a tetrahydropyranyl group, and further as another type (3-8)R 2 is a compound of 4-hydroxycyclohexyl, 4-hydroxy-4-methylcyclohexyl or tetrahydropyran-4-yl, further as another type of (3-9) R 2 is 4-hydroxycyclohexyl Further, as a compound of other forms (3-10), R 2 is a 4-hydroxy-4-methylcyclohexyl group, and further as another type of (3-11) R 2 is tetrahydropyran-4 a base compound, or a salt thereof.

(4)對於式(I)，R3 為-H之化合物或彼等之鹽。(4) For the formula (I), R 3 is a compound of -H or a salt thereof.

(5)上述(1)至(4)中任二個以上組合的化合物。作為該組合的型態例子，可舉出(5-1)上述(1)及(4)之化合物，作為其他型態之(5-2)上述(1)、(2)、及(4)之化合物，進一步作為其他型態之(5-3)上述(1)、(2)、(3)、及(4)之化合物，進一步作為其他型態之(5-4)上述(1-1)、(2-1)、(3-1)、及(4)之化合物，進一步作為其他型態之(5-5)上述(1-4)、(2-1)、(3-1)、及(4)之化合物，進一步作為其他型態之(5-6)上述(1-4)、(2-2)、(3-1)、及(4)之化合物，進一步作為其他型態之(5-7)上述(1-4)、(2-3)、(3-1)、及(4)之化合物，(5-8)上述(1-4)、(2-3)、(3-8)、及(4)之化合物，進一步作為其他型態之(5-9)選自上述(1-5)、(1-7)、(1-8)、(2-6)、(2-7)、(2-8)、(2-9)、(2-10)、(2-11)、(2-12)、(2-13)、(2-14)、(3-9)、(3-10)、(3-11)、及(4)所成群而不矛盾下任2個以上組合之化合物，或彼等之鹽。(5) A compound in which two or more of the above (1) to (4) are combined. Examples of the type of the combination include (5-1) the compounds of the above (1) and (4), and (5-2) the above (1), (2), and (4). The compound is further used as the compound of the above (1), (2), (3), and (4) in other forms, and further as (5-4) the above (1-1) Compounds of (2-1), (3-1), and (4), further as (5-5) above (1-4), (2-1), (3-1) And the compound of (4), further as another type (5-6) of the above compounds (1-4), (2-2), (3-1), and (4), further as other types (5-7) the compounds of the above (1-4), (2-3), (3-1), and (4), (5-8) the above (1-4), (2-3), The compounds of (3-8) and (4), further as other forms (5-9) are selected from the above (1-5), (1-7), (1-8), (2-6) , (2-7), (2-8), (2-9), (2-10), (2-11), (2-12), (2-13), (2-14), ( Compounds of 3-9), (3-10), (3-11), and (4) which are grouped together without contradicting two or more combinations, or salts thereof.

且，式(I)的化合物或其鹽的其他型態如以下所示。Further, other forms of the compound of the formula (I) or a salt thereof are shown below.

(6)對於式(I)，(6-1)-X-為式(II)之基，A為低級烷基之化合物，作為其他型態之(6-2)-X-為式(II)之基，A為乙基或異丙基之化合物，進一步作為其他型態之(6-3)-X-為式(II)之基，A為乙基之化合物，進一步作為其他型態之(6-4)-X-為式(II)之基，A為異丙基之化合物、或彼等之鹽。(6) For the formula (I), (6-1)-X- is a group of the formula (II), and A is a compound of a lower alkyl group, and (6-2)-X- is another formula (II-2)-X- a compound in which A is an ethyl group or an isopropyl group, and further as another type (6-3)-X- is a group of the formula (II), and A is an ethyl compound, and further as another type (6-4) -X- is a group of the formula (II), and A is a compound of isopropyl or a salt thereof.

(7)對於式(I)，(7-1)R1 為第4位碳由-W-Y-Z所取代之苯基，且作為其他取代基，第2位或第3位碳為可由R00 或-O-R00 所取代的苯基，-Y-為鍵之化合物，作為其他型態之(7-2)R1 為第4位碳由-W-Y-Z所取代之苯基，且作為其他取代基，第3位碳可由R00 或-O-R00 所取代的苯基，-W-為哌啶-1,4-二基(與-W-所結合之苯基以氮原子結合)或鍵，-Y-為鍵，-Z為第4位氮原子可由低級烷基所取代的哌嗪-1-基之化合物，進一步作為其他型態之(7-3)R1 為第4位碳由4-(4-甲基哌嗪-1-基)哌啶-1-基所取代之苯基，且作為其他取代基，第3位碳為可由甲基、三氟甲基、甲氧基、或乙氧基所取代的苯基之化合物，進一步作為其他型態之(7-4)R1 為3-甲基-4-{4-(4-甲基哌嗪-1-基)哌啶-1-基}苯基之化合物，進一步作為其他型態之(7-5)R1 為4-{4-(4-甲基哌嗪-1-基)哌啶-1-基}-3-(三氟甲基)苯基之化合物，進一步作為其他型態之(7-6)R1 為3-甲氧基-4-{4-(4-甲基哌嗪-1-基)哌啶-1-基}苯基之化合物，進一步作為其他型態之(7-7)R1 為3-乙氧基-4-{4-(4-甲基哌嗪-1-基)哌啶-1-基}苯基之化合物，進一步作為其他型態之(7-8)R1 為4-{4-(4-甲基哌嗪-1-基)哌啶-1-基}苯基之化合物，進一步作為其他型態之(7-9)R1 為第4位碳由4-甲基哌嗪-1-基或4-異丙基哌嗪-1-基所取代之苯基，且作為其他取代基，第3位碳可由甲基、三氟甲基、或甲氧基所取代的苯基之化合物，進一步作為其他型態之(7-10)R1 為3-甲基-4-(4-甲基哌嗪-1-基)苯基之化合物，進一步作為其他型態之(7-11)R1 為4-(4-甲基哌嗪-1-基)-3-(三氟甲基)苯基之化合物，進一步作為其他型態之(7-12)R1 為3-甲氧基-4-(4-甲基哌嗪-1-基)苯基之化合物，進一步作為其他型態之(7-13)R1 為4-(4-甲基哌嗪-1-基)苯基之化合物，進一步作為其他型態之(7-14)R1 為4-(4-異丙基哌嗪-1-基)-3-甲基苯基之化合物，進一步作為其他型態之(7-15)R1 為第3位碳由-SO2 -R00 所取代之苯基之化合物，進一步作為其他型態之(7-16)R1 為3-(甲基磺醯基)苯基之化合物，進一步作為其他型態之(7-17)R1 為第3位碳由-W-Y-Z所取代之苯基，且作為其他取代基，第4位碳可由-O-R00 所取代的苯基，-W-為鍵，-Y-為鍵之化合物，進一步作為其他型態之(7-18)R1 為第3位碳由4-甲基哌嗪-1-基所取代之苯基，且作為其他取代基，第4位碳可由甲氧基所取代的苯基之化合物，進一步作為其他型態之(7-19)R1 為4-甲氧基-3-(4-甲基哌嗪-1-基)苯基之化合物，進一步作為其他型態之(7-20)R1 為3-(4-甲基哌嗪-1-基)苯基之化合物，進一步作為其他型態之(7-21)R1 為2-甲氧基-4-{4-(4-甲基哌嗪-1-基)哌啶-1-基}苯基之化合物，進一步作為其他型態之(7-22)R1 為1-甲基吲唑-6-基之化合物，進一步作為其他型態之(7-23)R1 為4-嗎啉-4-基苯基之化合物，進一步作為其他型態之(7-24)R1 為4-(1-甲基哌啶-4-基)苯基之化合物，進一步作為其他型態之(7-25)R1 為4-{4-(環丙基甲基)哌嗪-1-基}-3-(三氟甲基)苯基之化合物，進一步作為其他型態之(7-26)R1 為4-{3-(二甲胺)吡咯烷-1-基}-3-(三氟甲基)苯基之化合物，或彼等之鹽。(7) For the formula (I), (7-1) R 1 is a phenyl group in which the carbon at the 4th position is substituted by -WYZ, and as other substituents, the carbon at the 2nd or the 3rd position may be R 00 or - a phenyl group substituted by OR 00 , a compound in which -Y- is a bond, and (7-2) R 1 as a phenyl group in which the 4th carbon is replaced by -WYZ, and as another substituent, the third The carbon in the position may be a phenyl group substituted by R 00 or -OR 00 , -W- is a piperidine-1,4-diyl group (the phenyl group bonded to -W- is bonded to a nitrogen atom) or a bond, and -Y- is The bond, -Z is a piperazine-1-yl compound in which the nitrogen atom at the 4th position may be substituted by a lower alkyl group, and further as another type (7-3), R 1 is a 4th carbon group by 4-(4- a phenyl group substituted with methylpiperazin-1-yl)piperidin-1-yl, and as other substituents, the carbon at the 3rd position may be a methyl group, a trifluoromethyl group, a methoxy group, or an ethoxy group. a substituted phenyl compound, further as another form of (7-4) R 1 is 3-methyl-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl} a compound of a phenyl group, further as another type of (7-5) R 1 is 4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}-3-(trifluoromethyl) a compound of a phenyl group, further as another type of (7-6)R 1 Is a compound of 3-methoxy-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl, further as another type of (7-7)R 1 a compound of 3-ethoxy-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl, further as another type of (7-8) R 1 is 4 -{4-(4-Methylpiperazin-1-yl)piperidin-1-yl}phenyl compound, further as another type of (7-9) R 1 is the 4th carbon from 4-A a phenyl group substituted with a piperazin-1-yl or a 4-isopropylpiperazin-1-yl group, and as other substituents, the carbon at the 3rd position may be substituted by a methyl group, a trifluoromethyl group, or a methoxy group. a compound of a phenyl group, further as a compound of other forms (7-10) wherein R 1 is a 3-methyl-4-(4-methylpiperazin-1-yl)phenyl group, further as another form (7-11) A compound wherein R 1 is 4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl, further as another type (7-12) R 1 is a compound of 3-methoxy-4-(4-methylpiperazin-1-yl)phenyl, further as another form of (7-13) R 1 is 4-(4-methylpiperazine-1 - compound-yl) phenyl, the other patterns of a further (7-14) R 1 is 4- (4-isopropyl-piperazin-1-yl) -3-methylphenyl of Compounds, further as the other patterns (7-15) R 1 bit 3 carbons substituted by a -SO 2 -R 00 the phenyl group of compounds, further as another type of (7-16) R 1 is a compound of 3-(methylsulfonyl)phenyl, further as another type (7-17), R 1 is a phenyl group in which the 3rd carbon is replaced by -WYZ, and as the other substituent, the 4th position A phenyl group in which carbon can be replaced by -OR 00 , a compound in which -W- is a bond, and -Y- is a bond, and further as another type (7-18), R 1 is a carbon at the 3rd position from 4-methylpiperazine. a phenyl group substituted with a -1- group, and as a further substituent, a compound of a phenyl group in which a carbon at the 4th position may be substituted by a methoxy group, and further as another type (7-19), R 1 is a 4-methoxy group. a compound of 3-(4-methylpiperazin-1-yl)phenyl, further as another form of (7-20)R 1 is 3-(4-methylpiperazin-1-yl)benzene a compound of the formula, further as another form (7-21) R 1 is 2-methoxy-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl Further, as a compound of other forms (7-22), R 1 is a 1-methyloxazol-6-yl group, and further as another form (7-23), R 1 is 4-morpholine-4. -ylphenyl Compounds, further as the other patterns (7-24) R 1 4- (1- methyl-piperidin-4-yl) phenyl the compound is further as another type of (7-25) R 1 is 4 a compound of -{4-(cyclopropylmethyl)piperazin-1-yl}-3-(trifluoromethyl)phenyl, further as another form (7-26) R 1 is 4-{3 a compound of -(dimethylamine)pyrrolidin-1-yl}-3-(trifluoromethyl)phenyl, or a salt thereof.

(8)對於式(I)，(8-1)R2 係由-OH及低級烷基所取代之環烷基之化合物，作為其他型態之(8-2)R2 係由-OH及低級烷基所取代之環己基之化合物，進一步作為其他型態之(8-3)R2 為第4位碳由-OH及低級烷基所取代之環己基之化合物，進一步作為其他型態之(8-4)R2 為第4位碳由-OH及甲基所取代之環己基之化合物，進一步作為其他型態之(8-5)R2 係由-OH所取代之環烷基之化合物，進一步作為其他型態之(8-6)R2 係由-OH所取代之環己基之化合物，進一步作為其他型態之(8-7)R2 為4-羥基環己基之化合物，進一步作為其他型態之(8-8)R2 可由低級烷基所取代的非芳香族雜環之化合物，進一步作為其他型態之(8-9)R2 可由低級烷基所取代的四氫吡喃基或哌啶基之化合物，進一步作為其他型態之(8-10)R2 為四氫吡喃-4-基之化合物，進一步作為其他型態之(8-11)R2 為第1位氮原子可由低級烷基所取代的哌啶-4-基之化合物，進一步作為其他型態之(8-12)R2 為1-甲基哌啶-4-基之化合物，進一步作為其他型態之(8-13)R2 為哌啶-4-基之化合物，或彼等之鹽。(8) For the formula (I), (8-1) R 2 is a compound of a cycloalkyl group substituted by -OH and a lower alkyl group, and (8-2) R 2 of another type is derived from -OH and a compound of a cyclohexyl group substituted by a lower alkyl group, further as another type of (8-3) R 2 is a compound of a cyclohexyl group in which a carbon at the 4th position is substituted by -OH and a lower alkyl group, and further as another type (8-4) R 2 is a compound of a cyclohexyl group in which a carbon at the 4th position is substituted by -OH and a methyl group, and further as a cycloalkyl group in which (8-5) R 2 is substituted by -OH. Further, the compound is further used as a compound of another type (8-6) R 2 -based cyclohexyl group substituted by -OH, and further as a compound of other forms (8-7) R 2 is a 4-hydroxycyclohexyl group, further As another non-aromatic heterocyclic compound in which (8-8) R 2 may be substituted by a lower alkyl group, tetrahydropyridyl which may be substituted by a lower alkyl group as another type (8-9) R 2 a compound of a thiol or piperidinyl group, further as another compound of the formula (8-10), wherein R 2 is a tetrahydropyran-4-yl group, and further as another type (8-11) R 2 is the first The nitrogen atom can be replaced by a lower alkyl group. The compound 4-yl, in yet another of the patterns (8-12) R 2 compound 1-methyl-piperidin-4-yl it is, the patterns for an even further (8-13) R 2 is a piperazinyl a compound of the pyridine-4-yl group, or a salt thereof.

(9)對於式(I)，R3 為-H之化合物或彼等之鹽。(9) For the formula (I), R 3 is a compound of -H or a salt thereof.

(10)上述(6-3)的化合物或彼等之鹽。(10) A compound of the above (6-3) or a salt thereof.

(11)上述(7-4)、(7-5)、(7-6)、(7-7)、(7-8)、(7-10)、(7-13)、或(7-14)的化合物、或彼等之鹽。(11) The above (7-4), (7-5), (7-6), (7-7), (7-8), (7-10), (7-13), or (7- 14) a compound, or a salt thereof.

(12)上述(8-4)、(8-7)、(8-10)、或(8-13)的化合物、或彼等之鹽。(12) A compound of the above (8-4), (8-7), (8-10), or (8-13), or a salt thereof.

(13)(13-1)上述(6)至(9)中任二個以上組合之化合物，作為其他型態之(13-2)上述(9)至(12)中任二以上組合之化合物，或彼等之鹽。(13) (13-1) A compound in which two or more of the above (6) to (9) are combined, and as a compound of two or more of the above (9) to (12) in another form (13-2) Or their salt.

作為包含於本發明之具體化合物例子，可舉出以下所示化合物。Examples of specific compounds included in the present invention include the compounds shown below.

6-乙基-5-[(反式-4-羥基環己基)胺基]-3-{[4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-({4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、5-[(反式-4-羥基環己基)胺基]-6-異丙基-3-{[4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-({4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]-3-(三氟甲基)苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、5-[(反式-4-羥基環己基)胺基]-6-異丙基-3-({4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]-3-(三氟甲基)苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-[(順式-4-羥基-4-甲基環己基)胺基]-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-{[4-(4-異丙基哌嗪-1-基)-3-甲基苯基]胺基}吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基-4-甲基環己基)胺基]-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、6-乙基-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、6-氯-5-[(反式-4-羥基環己基)胺基]-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、6-乙基-3-({4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、6-乙基-3-({3-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、6-異丙基-3-({4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、6-乙基-3-{[3-氟-4-(4-甲基哌嗪-1-基)苯基]胺基}-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、6-異丙基-3-{[3-甲氧基-4-(4-甲基哌嗪-1-基)苯基]胺基}-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、6-異丙基-3-{[4-(4-甲基哌嗪-1-基)苯基]胺基}-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、或6-乙基-3-({3-甲基-4-[4-(1-甲基哌啶-4-基)哌嗪-1-基]苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、或彼等之鹽。6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2 -Procarbamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidine) -1-yl]phenyl}amino)pyrazine-2-carboxamide, 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-( 4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3- ({4-[4-(4-Methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine -1-yl]phenyl}amino)pyrazine-2-carboxamide, 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[ 4-(4-Methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide, 6-ethyl- 5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidine -1-yl]phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4 -isopropylpiperazin-1-yl)-3-methylbenzene Amino}pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4) -[4-(4-Methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-3-({3-A 4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino) Pyrazine-2-carboxamide, 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylperidine) Pyrazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-3-({4-[4-(4-methylpiperazine)- 1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-ethyl-3 -({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran 4-ylamino)pyrazine-2-carboxamide, 6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl] Phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-ethyl-3-{[3-fluoro-4-(4 -methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-isopropyl-3 -{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydrogen -2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino }-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, or 6-ethyl-3-({3-methyl-4-[4-(1) -methylpiperidin-4-yl)piperazin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, Or their salt.

且作為包含於本發明之具體化合物例子，亦可舉出選自以下所示化合物群P、及化合物群Q的化合物。Further, examples of the specific compound to be contained in the present invention include compounds selected from the group consisting of P and the compound group Q shown below.

化合物群P：6-乙基-5-[(反式-4-羥基環己基)胺基]-3-({4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-{[4-(4-甲基哌嗪-1-基)-3-(三氟甲基)苯基]胺基}吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-({4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]-3-(三氟甲基)苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-{[3-甲基-4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-[(順式-4-羥基-4-甲基環己基)胺基]-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-{[4-(4-異丙基哌嗪-1-基)-3-甲基苯基]胺基}吡嗪-2-甲醯胺、3-({3-乙氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)-6-乙基-5-[(反式-4-羥基環己基)胺基]吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基-4-甲基環己基)胺基]-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、6-乙基-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、6-乙基-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)-5-(哌啶-4-基胺基)吡嗪-2-甲醯胺、6-乙基-3-{[4-(4-甲基哌嗪-1-基)苯基]胺基}-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、6-乙基-3-({4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、及6-乙基-3-({3-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、以及這些鹽所成群。Compound group P: 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidine- 1-yl]phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4- Methyl piperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl) Amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine 2-carbamamine, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-methyl-4-(4-methylpiperazin-1- Phenyl]amino}pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4- [4-(4-Methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-5-[(cis-4 -hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl} Amino)pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpiperazine-1 -yl)-3-methylphenyl]amino}pyrazine-2-carboxamide, 3-({3-ethoxy-4-[4-(4-methylpiperazin-1-yl)) Piperidin-1-yl]phenyl}amino)-6- 5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl) Amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamidine Amine, 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-( Tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazine)- 1-yl)piperidin-1-yl]phenyl}amino)-5-(piperidin-4-ylamino)pyrazine-2-carboxamide, 6-ethyl-3-{[4- (4-Methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-ethyl- 3-({4-[4-(4-Methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamine Pyrazine-2-carboxamide, and 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl) Phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, and a mixture of these salts.

化合物群Q：6-乙基-5-[(反式-4-羥基環己基)胺基]-3-{[3-(甲基磺醯基)苯基]胺基}吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基-4-甲基環己基)胺基]-3-{[3-(甲基磺醯基)苯基]胺基}吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-({2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-{[4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-[(1-甲基-1H-吲唑-6-基)胺基]吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-({3-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、5-[(反式-4-羥基環己基)胺基]-6-異丙基-3-{[4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-{[3-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-{[3-甲氧基-4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-[(4-嗎啉-4-基苯基)胺基]吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-{[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基環己基)胺基]-3-{[4-(1-甲基哌啶-4-基)苯基]胺基}吡嗪-2-甲醯胺、5-[(反式-4-羥基環己基)胺基]-6-異丙基-3-({4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]-3-(三氟甲基)苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-[(順式-4-羥基-4-甲基環己基)胺基]-3-{[3-甲基-4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺、3-({4-[4-(環丙基甲基)哌嗪-1-基]-3-(三氟甲基)苯基}胺基)-6-乙基-5-[(反式-4-羥基環己基)胺基]吡嗪-2-甲醯胺、3-({4-[3-(二甲胺)吡咯烷-1-基]-3-(三氟甲基)苯基}胺基)-6-乙基-5-[(反式-4-羥基環己基)胺基]吡嗪-2-甲醯胺、6-乙基-5-[(順式-4-乙基-4-羥基環己基)胺基]-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-乙基-4-羥基環己基)胺基]-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-[(順式-4-羥基-4-異丙基環己基)胺基]-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-[(反式-4-羥基-4-異丙基環己基)胺基]-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺、及6-乙基-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)-5-[(1-甲基哌啶-4-基)胺基]吡嗪-2-甲醯胺、以及這些鹽所成群。Compound Group Q: 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2- Formamide, 6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino} Pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({2-methoxy-4-[4-(4-) Piperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amine ]-3-{[4-(4-Methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxyl) Cyclohexyl)amino]-3-[(1-methyl-1H-indazol-6-yl)amino]pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4) -hydroxycyclohexyl)amino]-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyridinium Pyrazine-2-carboxamide, 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)benzene Amino}pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(4-methylpiperazine- 1-yl)phenyl]amino}pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-methoxy 4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amine ]-3-[(4-morpholin-4-ylphenyl)amino]pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino] -3-{[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide, 6-ethyl-5-[(reverse) 4-Hydroxycyclohexyl)amino]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide, 5-[(reverse) 4-Hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-( Trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-{ [3-Methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide, 3-({4-[4-(cyclopropylmethyl) Piperazine-1-yl]-3-(trifluoromethyl)phenyl}amino)-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2- Formamide, 3-({4-[3-(dimethylamine)pyrrolidin-1-yl]-3-(trifluoromethyl)phenyl}amino)-6-ethyl-5-[( Trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide, 6-ethyl-5-[(cis-4-ethyl-4-hydroxycyclohexyl)amino]-3- ({3-methyl 4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-5-[(reverse 4-ethyl-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl] Phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-5-[(cis-4-hydroxy-4-isopropylcyclohexyl)amino]-3-({3-A 4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-5-[( Trans-4-hydroxy-4-isopropylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1- (phenyl)amino)pyrazine-2-carboxamide, and 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)perylene Pyridin-1-yl]phenyl}amino)-5-[(1-methylpiperidin-4-yl)amino]pyrazine-2-carboxamide, and a mixture of these salts.

於式(I)之化合物中，依取代基種類，存在互變異構物或幾何異構物(含有具有環烷基等飽和環基之化合物的順式-反式異構物)。本說明書中，雖僅記載式(I)的化合物之一異構物形態，但本發明亦包含此以外之異構物、異構物之分離者、或這些混合物。Among the compounds of the formula (I), depending on the kind of the substituent, there are tautomers or geometric isomers (cis-trans isomers containing a compound having a saturated cyclic group such as a cycloalkyl group). In the present specification, only one isomeric form of the compound of the formula (I) is described, but the present invention also includes the isomers, the separators of the isomers, or a mixture thereof.

又，於式(I)之化合物具有不對稱碳原子或軸不對稱時，存在基於此的光學異構物。本發明亦包含式(I)化合物之光學異構物經分離者、或這些混合物。Further, when the compound of the formula (I) has an asymmetric carbon atom or an axis asymmetry, an optical isomer based thereon is present. The invention also encompasses optical isomers of the compounds of formula (I), or mixtures thereof.

且，本發明亦包含式(I)所示化合物的製藥學上可被接受的前驅藥物。所謂製藥學上可被接受的前驅藥物為，具有藉由加溶劑分解或生理學的條件下轉變為胺基、羥基、羧基等的基之化合物。作為形成前驅藥物之基，例如可舉出Prog. Med.,5,2157-2161(1985)、或「醫藥品之開發」(廣川書店，1990年)第7卷分子設計163-198所記載之基。Moreover, the invention also encompasses a pharmaceutically acceptable prodrug of a compound of formula (I). The pharmaceutically acceptable precursor drug is a compound having a group which is converted into an amine group, a hydroxyl group, a carboxyl group or the like by solvolysis or physiological conditions. Examples of the group forming the precursor drug include those described in Prog. Med., 5, 2157-2161 (1985), or "Development of Pharmaceutical Products" (Guangchuan Bookstore, 1990), Volume 7, Molecular Designs 163-198. base.

又，所謂式(I)之化合物的鹽為，式(I)的化合物之製藥學上可被接受的鹽，藉由取代基之種類，有時會形成酸加成鹽或與鹼之加成鹽。具體可舉出與鹽酸、氫溴酸、碘化氫酸、硫酸、硝酸、磷酸等無機酸、或與甲酸、乙酸、丙酸、丁酸、丙二酸、琥珀酸、富馬酸、馬來酸、乳酸、蘋果酸、苦杏仁酸、酒石酸、二苯甲醯基酒石酸、二甲苯甲醯基酒石酸、檸檬酸、甲磺酸、乙磺酸、苯磺酸、p-甲苯磺酸、天冬胺酸、麩胺酸等有機酸之酸加成鹽、與鈉、鉀、鎂、鈣、鋁等無機鹼、甲基胺、乙基胺、乙醇胺、賴胺酸、鳥胺酸等有機鹼之鹽、與乙醯基亮胺酸等各種胺基酸及胺基酸衍生物之鹽或銨鹽等。Further, the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I), and an acid addition salt or an addition to a base may be formed depending on the kind of the substituent. salt. Specific examples thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, hydrogen iodide, sulfuric acid, nitric acid, and phosphoric acid, or with formic acid, acetic acid, propionic acid, butyric acid, malonic acid, succinic acid, fumaric acid, and Malay. Acid, lactic acid, malic acid, mandelic acid, tartaric acid, benzhydryl tartaric acid, xylyl decyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic An acid addition salt of an organic acid such as aminic acid or glutamic acid, and an inorganic base such as sodium, potassium, magnesium, calcium or aluminum, an organic base such as methylamine, ethylamine, ethanolamine, lysine or ornithine Salts or ammonium salts of various amino acids and amino acid derivatives such as salts and etidyl leucine.

且，本發明亦包含式(I)的化合物及其鹽之各種水合物或溶劑合物、及結晶多形之物質。又，本發明亦包含以種種放射性或非放射性同位素體所標識之化合物。Further, the present invention also encompasses various hydrates or solvates of the compound of the formula (I) and salts thereof, and a crystalline polymorph. Further, the invention also encompasses compounds identified by various radioactive or non-radioactive isotopes.

式(I)的化合物及該製藥學上可被接受的鹽可藉由利用以該基本骨架或取代基種類為準的特徴，使用種種公知合成法而製造。此時，依據官能基之種類，將該官能基在原料至中間體的階段取代為適當保護基(可容易轉換為該官能基之基)時，於製造技術上具有效果。作為如此保護基，例如可舉出Greene及Wuts著之「Greene’s Protective Groups in Organic Synthesis(第4版、2007年)」所記載之保護基等，配合這些反應條件經適宜選擇後使用即可。如此方法中，導入該保護基並進行反應後，視必要藉由除去保護基可得到所望化合物。The compound of the formula (I) and the pharmaceutically acceptable salt can be produced by using various known synthetic methods using the characteristics of the basic skeleton or the substituent. At this time, depending on the kind of the functional group, when the functional group is substituted at a stage of a raw material to an intermediate to a suitable protecting group (which can be easily converted into a group of the functional group), it is effective in a manufacturing technique. As such a protective group, for example, a protecting group described in "Greene's Protective Groups in Organic Synthesis (4th edition, 2007)" by Greene and Wuts may be used, and these reaction conditions may be appropriately selected and used. In such a method, after introducing the protecting group and carrying out the reaction, the desired compound can be obtained by removing the protecting group as necessary.

又，式(I)的化合物之前驅藥物與上述保護基同樣地，可由在原料至中間體之階段導入特定基、或使用所得之式(I)的化合物進一步進行反應而可製造。反應可藉由使用一般酯化、醯胺化、脫水等斯業者公知的方法而進行。Further, the compound precursor compound of the formula (I) can be produced by further introducing a specific group at the stage of the raw material to the intermediate or using the obtained compound of the formula (I) in the same manner as the above-mentioned protecting group. The reaction can be carried out by a method known in the art, such as general esterification, amide amination, and dehydration.

以下說明式(I)之化合物的代表性製造法。各製法亦可參考附於該說明的參考文獻進行。且，本發明的製造法並未限定於以下所示例子。A representative production method of the compound of the formula (I) is explained below. The various methods can also be referred to the references attached to the description. Further, the production method of the present invention is not limited to the examples shown below.

(第1製法)(the first method)

(式中，-LA 表示脫離基，例如可舉出低級烷基磺醯基)(wherein, -L A represents a leaving group, and for example, a lower alkylsulfonyl group is exemplified)

本製法為反應化合物(1a)與化合物(2)，製造本發明化合物(I-a)之方法。The process of the present invention is a process for producing the compound (I-a) of the present invention by reacting the compound (1a) with the compound (2).

該反應中，將化合物(1a)與化合物(2)以等量或一方過剩量下使用，將彼等混合物，於對反應為惰性之溶劑中、或無溶劑下，自冷卻下至加熱迴流下，較佳為0℃～200℃中，一般為進行0.1小時～5天之攪拌。使用微波反應裝置進行反應時，因反應可順利地進行故較為有利。作為此所使用的溶劑例子，若對反應為惰性的溶劑即可，並無特別限定，可舉出苯、甲苯、二甲苯等芳香族烴類、二乙醚、四氫呋喃(THF)、二噁烷、二甲氧基乙烷等醚類、1,2-二氯乙烷、氯仿等的鹵化烴類、甲醇、乙醇、2-丙醇等醇類、1-甲基-2-吡咯烷酮(NMP)、N,N-二甲基甲醯胺(DMF)、N,N-二甲基乙醯胺(DMA)、1,3-二甲基-2-咪唑烷酮(DMI)、二甲基亞碸(DMSO)、乙腈及這些混合物。在三乙胺、N,N-二異丙基乙基胺或N-甲基嗎啉等有機鹼、或碳酸鉀、碳酸鈉或氫氧化鉀等無機鹼的存在下進行反應時，因反應可順利地進行故較為有利。In the reaction, the compound (1a) and the compound (2) are used in an equal amount or in an excess amount, and the mixture is allowed to stand in a solvent inert to the reaction or in the absence of a solvent, from cooling to heating under reflux. Preferably, it is from 0 ° C to 200 ° C, and is generally stirred for 0.1 to 5 days. When the reaction is carried out using a microwave reaction apparatus, it is advantageous because the reaction proceeds smoothly. The solvent to be used in the reaction is not particularly limited, and examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether, tetrahydrofuran (THF), and dioxane. An ether such as dimethoxyethane; a halogenated hydrocarbon such as 1,2-dichloroethane or chloroform; an alcohol such as methanol, ethanol or 2-propanol; or 1-methyl-2-pyrrolidone (NMP); N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl hydrazine (DMSO), acetonitrile and these mixtures. When the reaction is carried out in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine or N-methylmorpholine or an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide, the reaction may be carried out. It is more advantageous to carry out smoothly.

又，在如上述鹼之存在下進行反應時，依據原料化合物之性質等，例如會使原料化合物分解等期待反應不會進行、或難以進行之情況產生。此時，鹽酸或氫溴酸等無機酸、乙酸或丙酸等有機酸、甲磺酸或p-甲苯磺酸等磺酸類的存在下進行反應時，因反應可順利進行故為有利狀況。且，-LA 為低級烷基磺醯基時，S原子以奧克森(註冊商標)、m-氯過安息香酸(mCPBA)、過乙酸等種種氧化劑進行氧化，轉換為低級烷基亞磺醯基或低級烷基磺醯基後與化合物(2)進行反應之方法，亦因反應可順利地進行故較為有利。In addition, when the reaction is carried out in the presence of the above-mentioned base, depending on the nature of the raw material compound or the like, for example, the desired reaction such as decomposition of the raw material compound may not proceed or may be difficult to proceed. In this case, when a reaction is carried out in the presence of an inorganic acid such as hydrochloric acid or hydrobromic acid, an organic acid such as acetic acid or propionic acid, or a sulfonic acid such as methanesulfonic acid or p-toluenesulfonic acid, the reaction proceeds smoothly, which is advantageous. Further, when -L A is a lower alkylsulfonyl group, the S atom is oxidized by various oxidizing agents such as Oxon (registered trademark), m-chloroperoxybenzoic acid (mCPBA), peracetic acid, and converted into a lower alkyl sulfinic acid. The method of reacting the compound (2) with a mercapto group or a lower alkylsulfonyl group is also advantageous because the reaction can be carried out smoothly.

[文獻][literature]

S. R. Sandler及W. Karo著、「Organic Functional Group Preparations」、第2版、第1卷、Academic Press Inc.、1991年S. R. Sandler and W. Karo, "Organic Functional Group Preparations", 2nd Edition, Volume 1, Academic Press Inc., 1991

日本化學會「實驗化學講座(第5版)」14卷(2005年)(丸善)The Chemical Society of Japan, "Experimental Chemistry Lecture (5th Edition)", Volume 14 (2005) (Maruzen)

(第2製法)(the second method)

(式中，-LB 表示脫離基，例如可舉出F、Cl等的鹵素、甲磺醯氧基、p-甲苯磺醯氧基、三氟甲磺醯氧基等磺醯氧基、或低級烷基磺醯基或低級烷基磺醯基)(wherein, -L B represents a leaving group, and examples thereof include a halogen such as F or Cl, a sulfonyloxy group such as a methanesulfonyloxy group, a p-toluenesulfoxy group or a trifluoromethanesulfonyloxy group; Lower alkylsulfonyl or lower alkylsulfonyl)

本製法為將化合物(1b)與化合物(2)進行反應，製造本發明化合物(I-b)之方法。The present process is a process for producing the compound (I-b) of the present invention by reacting the compound (1b) with the compound (2).

該反應中，可依據第1製法的方法進行。This reaction can be carried out according to the method of the first production method.

(原料合成1)(Material synthesis 1)

(式中，-LC 表示脫離基，例如可舉出F、Cl等的鹵素、甲磺醯氧基、p-甲苯磺醯氧基、三氟甲磺醯氧基等磺醯氧基。又，式中，RA 表示醯基、苯甲基、低級烷基或-H，M表示鹼金屬。)(In the formula, -L C represents a leaving group, and examples thereof include a halogen such as F, Cl or the like, a sulfonyloxy group such as a methanesulfonyloxy group, a p-toluenesulfoxy group or a trifluoromethanesulfonyloxy group. Wherein R A represents a mercapto group, a benzyl group, a lower alkyl group or -H, and M represents an alkali metal.

本製法為對於將化合物(3)與化合物(4)進行反應所得之化合物(5)，反應化合物(6)後，賦予脫保護反應而除去RA 後製造化合物(1a)之方法。The production method is a method in which the compound (5) obtained by reacting the compound (3) with the compound (4) and the compound (6) are reacted, and then the deprotection reaction is carried out to remove the R A to produce the compound (1a).

得到化合物(5)之反應中，可依據第1製法的方法進行。又，得到化合物(1a)之反應中，使用第1製法之方法，可使化合物(6)或使用系統中產生化合物(6)之試藥進行反應，其後，例如可適宜選擇Greene及Wuts著、「Greene’s Protective Groups in Organic Synthesis(第4版，2007年)」所記載之反應條件進行脫保護反應。其中，作為化合物(6)之例子，可舉出乙酸鈉或甲氧化鈉。且，取代化合物(6)，使用過氧化氫水進行反應後，以鹽酸等進行酸處理亦可製造化合物(1a)。The reaction for obtaining the compound (5) can be carried out according to the method of the first production method. Further, in the reaction for obtaining the compound (1a), the compound (6) or the reagent for producing the compound (6) in the system can be reacted by the method of the first production method, and thereafter, for example, Greene and Wuts can be appropriately selected. The reaction conditions described in "Greene's Protective Groups in Organic Synthesis (4th edition, 2007)" were subjected to a deprotection reaction. Among them, examples of the compound (6) include sodium acetate or sodium methoxide. Further, the compound (1a) can be produced by subjecting the compound (6) to a reaction using hydrogen peroxide water, followed by acid treatment with hydrochloric acid or the like.

(原料合成2)(Material Synthesis 2)

本製法為反應化合物(7)與化合物(4)後製造化合物(1b)之方法。The present process is a process for producing the compound (1b) by reacting the compound (7) with the compound (4).

該反應中，可使用第1製法之方法。In the reaction, the method of the first production method can be used.

式(I)的化合物可作為游離化合物、該製藥學上可被接受的鹽、水合物、溶劑合物、或結晶多形的物質而被分離後純化。式(I)之化合物的製藥學上可被接受的鹽亦可藉由常法之造鹽反應而製造。The compound of the formula (I) can be isolated and purified as a free compound, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystalline polymorph. The pharmaceutically acceptable salts of the compounds of formula (I) can also be prepared by conventional salt-forming reactions.

分離、純化可使用萃取、分別結晶化、各種劃分層析法等一般化學操作而進行。Separation and purification can be carried out by general chemical operations such as extraction, separate crystallization, and various division chromatography.

各種異構物可藉由選擇適當原料化合物而製造、或利用異構物間之物理化學性質差而可分離。例如光學異構物為藉由一般光學分割法(例如導出與光學活性鹼或酸之立體異構物鹽再進行分別結晶化、或使用鏡像異構物層析管柱(chiral column)等層析法等)，導出光學性單純之異構物。又，亦可由適當光學活性原料化合物而製造。The various isomers can be produced by selecting an appropriate starting compound or by utilizing poor physicochemical properties between the isomers. For example, the optical isomer is subjected to general optical division (for example, derivatization with an optically active base or an acid stereoisomer salt, or chromatography using a mirror-isomer chromatography column) Method, etc., to derive optically pure isomers. Further, it can also be produced from a suitable optically active starting material compound.

式(I)的化合物之藥理活性可藉由以下試驗做確認。若無特別要求，以下所示試驗例可依據歐洲專利申請公開EP 1914240號公報所記載之方法或其他公知方法實施，使用購得之試藥或套組等時，可依據販賣品的說明書實施。且，所謂EML4-ALK融合蛋白質v1為，由專利文獻1的配列號碼2所示胺基酸配列所成之聚肽，所謂EML4-ALK融合蛋白質v3為，由專利文獻1的配列號碼130所示胺基酸配列所成之聚肽。The pharmacological activity of the compound of formula (I) can be confirmed by the following test. Unless otherwise specified, the test examples shown below can be carried out according to the method described in the European Patent Application Publication No. EP 1914240 or other known methods, and when the purchased reagent or kit is used, it can be carried out according to the instructions of the merchandise. In addition, the EML4-ALK fusion protein v1 is a peptide formed by the arrangement of the amino acid shown in the alignment number 2 of Patent Document 1, and the EML4-ALK fusion protein v3 is represented by the alignment number 130 of Patent Document 1. The amino acid is formulated into a peptide formed.

試驗例1 EML4-ALK融合蛋白質之激酶活性的阻斷活性評估Test Example 1 Evaluation of blocking activity of kinase activity of EML4-ALK fusion protein

插入EML4-ALK融合蛋白質v1之cDNA的表現質體由由FLAG-EML4-ALKv1/pMX-iresCD8製作出重組反轉錄病毒，對老鼠淋巴系細胞株BA/F3細胞進行感染。使用細胞分離用磁珠試藥及純化管柱(對於CD8之磁珠結合單株抗體與MiniMACS純化管柱；皆為Miltenyi Biotec公司)，純化細胞表面CD8表現細胞，得到EML4-ALK融合蛋白質v1表現BA/F3細胞。由本細胞純化EML4-ALK融合蛋白質v1提供於激酶活性評估上。將對於EML4-ALK融合蛋白質v1之肽基質的磷氧化活性使用激酶活性檢出套組(HTRF KinEASE-TK；Cisbio公司)進行檢討。將被驗化合物以最終濃度為1000 nM至0.3 nM的8階段添加於含有酵素蛋白之反應液中，其次添加ATP並進行1小時反應。ATP濃度使用100μM。製作出含有酵素蛋白但未含有被驗化合物之反應液(取代被驗化合物僅添加溶劑之DMSO0.4%)，添加ATP、或未添加下進行相同反應。被驗化合物未添加之ATP未添加及添加時的磷氧化計算各為100%阻斷及0%阻斷，將當50%阻斷時的被驗化合物濃度(IC50 )以邏輯回歸法算出。Expression plastid of cDNA inserted into EML4-ALK fusion protein v1 A recombinant retrovirus was produced from FLAG-EML4-ALKv1/pMX-iresCD8, and the mouse lymphoid cell line BA/F3 cells were infected. The cell-separating magnetic beads and the purification column (for the magnetic beads combined with the CD8 and the MiniMACS purification column; all of which are Miltenyi Biotec) were used to purify the cell surface CD8 expressing cells to obtain the EML4-ALK fusion protein v1 expression. BA/F3 cells. Purification of EML4-ALK fusion protein v1 from this cell is provided for kinase activity assessment. The phosphorylation activity of the peptide matrix for EML4-ALK fusion protein v1 was reviewed using a kinase activity detection kit (HTRF KinEASE-TK; Cisbio). The test compound was added to the reaction solution containing the enzyme protein in an 8-stage final concentration of 1000 nM to 0.3 nM, and ATP was added thereto and the reaction was carried out for 1 hour. The ATP concentration was 100 μM. A reaction solution containing the enzyme protein but not containing the test compound (0.4% of DMSO in which the test compound was added only with a solvent) was prepared, and ATP was added or the same reaction was carried out without addition. The phosphorus oxidation calculation when the ATP was not added and the addition of the test compound was 100% blocking and 0% blocking, respectively, and the test compound concentration (IC 50 ) at 50% blocking was calculated by a logistic regression method.

其結果對於幾個本發明化合物而言，顯示對於EML4-ALK融合蛋白質v1之激酶活性的阻斷活性。對於幾個本發明化合物，其IC50 值如表1所示。Ex表示實施例號碼。且，表中所謂Compound X為國際公開第WO 2009/136995號手冊所記載之實施例174的化合物之消旋異構物(rac-2-{[(1R,2S)-2-胺環戊基]胺基}-4-{[4'-(嗎啉-4-基)聯苯-4-基]胺基}嘧啶-5-甲醯胺)，所謂Compound Y為國際公開第WO 00/76980號手冊所記載之實施例26-22的化合物(5-{[2-(二甲胺)乙基]胺基}-6-乙基-3-[(3-甲基苯基)胺基]吡啶-2-甲醯胺)。The results show blocking activity against the kinase activity of the EML4-ALK fusion protein v1 for several compounds of the invention. For several compounds of the present invention, an IC 50 values shown in Table 1. Ex represents the embodiment number. Further, the compound X in the table is a racemic isomer of the compound of Example 174 described in the handbook of International Publication No. WO 2009/136995 (rac-2-{[(1R,2S)-2-aminecyclopentyl) Amino}-4-{[4'-(morpholin-4-yl)biphenyl-4-yl]amino}pyrimidine-5-carboxamide), called Compound Y is International Publication No. WO 00/76980 The compound of Example 26-22 described in the manual (5-{[2-(dimethylamine)ethyl]amino}-6-ethyl-3-[(3-methylphenyl)amino] Pyridine-2-carboxamide).

試驗例2 EML4-ALK融合蛋白質依賴性細胞增殖之抑制活性評估Test Example 2 Evaluation of inhibitory activity of EML4-ALK fusion protein-dependent cell proliferation

EML4-ALK融合蛋白質v1表現BA/F3細胞於IL-3非存在下亦可增殖。即，本細胞為EML4-ALK融合蛋白質v1依賴性增殖之細胞。The EML4-ALK fusion protein v1 expresses that BA/F3 cells can also proliferate in the absence of IL-3. That is, the present cell is a cell in which the EML4-ALK fusion protein is v1-dependently proliferated.

於96格培養皿(Iwaki)中，將表現EML4-ALK融合蛋白質v1之BA/F3細胞，播種於含有10%牛胚胎血清之RPMI1640培養基(Invitrogen)至每1格為500細胞。作為被驗化合物(最終濃度10μM至0.1nM)及陰性對照，添加被驗化合物之溶劑的DMSO。於5%CO2 存在下在37℃進行2天培養，添加細胞數測定試藥(AlmarBlue；Biosource公司)並經150分鐘培養後，使用發光測定裝置(Safire；Tecan公司)，以添加試藥之方法測定螢光強度。僅培養基之測定值及陰性對照之測定值各為100%抑制及0%抑制，算出被驗化合物之抑制率，將50%抑制濃度(IC50 值)由邏輯回歸法求得。BA/F3 cells expressing EML4-ALK fusion protein v1 were seeded in RPMI1640 medium (Invitrogen) containing 10% bovine embryo serum to 96 cells per square in 96-well culture dishes (Iwaki). As a test compound (final concentration: 10 μM to 0.1 nM) and a negative control, DMSO of the solvent of the test compound was added. The cells were cultured at 37 ° C for 2 days in the presence of 5% CO 2 , and the cell number assay reagent (Almar Blue; Biosource) was added and cultured for 150 minutes, and then a luminescence assay device (Safire; Tecan) was used to add the reagent. Method The fluorescence intensity was measured. Only the measured values of the medium and the measured values of the negative control were 100% inhibition and 0% inhibition, and the inhibition rate of the test compound was calculated, and the 50% inhibitory concentration (IC 50 value) was determined by logistic regression.

其結果，幾個本發明化合物對於表現EML4-ALK融合蛋白質v1之BA/F3細胞顯示增殖抑制活性。對於幾個本發明化合物之IC50 值如表2所示。Ex表示實施例號碼。且，表中所謂Compound X及Compound Y表示試驗例1所記載之化合物。As a result, several of the compounds of the present invention showed proliferation inhibitory activity against BA/F3 cells expressing the EML4-ALK fusion protein v1. The IC 50 values for several of the compounds of the invention are shown in Table 2. Ex represents the embodiment number. Further, Compound X and Compound Y in the table indicate the compounds described in Test Example 1.

由上述試驗例1～2的結果確認本發明化合物具有EML4-ALK融合蛋白質v1的激酶活性之阻斷活性及EML4-ALK融合蛋白質v1表現BA/F3細胞之增殖抑制活性。另一方面，試驗例1所記載之Compound X及Compound Y與本發明化合物比較，確認EML4-ALK融合蛋白質v1的激酶活性之阻斷活性及EML4-ALK融合蛋白質v1表現BA/F3細胞的增殖抑制活性極弱。From the results of the above Test Examples 1 and 2, it was confirmed that the compound of the present invention has the blocking activity of the kinase activity of the EML4-ALK fusion protein v1 and the EML4-ALK fusion protein v1 exhibits the proliferation inhibitory activity of the BA/F3 cells. On the other hand, Compound X and Compound Y described in Test Example 1 confirmed that the blocking activity of the kinase activity of EML4-ALK fusion protein v1 and the inhibition of proliferation of BA/F3 cells by EML4-ALK fusion protein v1 were compared with the compound of the present invention. Very weak activity.

試驗例3對於EML4-ALK融合蛋白質依賴性細胞之抗腫瘤試驗(in vivo)Test Example 3 Anti-tumor test for EML4-ALK fusion protein-dependent cells (in vivo)

將插入EML4-ALK融合蛋白質v1的cDNA之表現質體EML4-ALKv1/pMXS藉由以磷酸鈣法導入於3T3纖維芽細胞，得到EML4-ALK融合蛋白質v1表現3T3細胞。將懸浮於PBS之EML4-ALK融合蛋白質v1表現3T3細胞3×106 個注射於5週齡的雄性Balb/c裸鼠(日本Charles River公司)之背部皮下而植入。植入後7天，開始投與被驗化合物。試驗以溶劑群及化合物投與群各4匹進行，於0.5%甲基纖維素的溶劑懸浮被驗化合物，以10 mg/kg經口投與。投與為5日間1天進行1次，將體重及腫瘤徑以隔日進行測定。使用以下式子算出腫瘤體積。The expression plastid EML4-ALKv1/pMXS of the cDNA into which the EML4-ALK fusion protein v1 was inserted was introduced into 3T3 fibroblasts by the calcium phosphate method, and the EML4-ALK fusion protein v1 was expressed as 3T3 cells. The EML4-ALK fusion protein v1 suspended in PBS showed 3×3 6 3T3 cells injected into the back of a 5-week-old male Balb/c nude mouse (Charles River, Japan) and implanted. Seven days after implantation, the test compound was administered. The test was carried out in a solvent group and a compound administration group of 4 mice, and the test compound was suspended in a solvent of 0.5% methylcellulose, and orally administered at 10 mg/kg. The administration was performed once a day for 5 days, and the body weight and the tumor diameter were measured every other day. The tumor volume was calculated using the following formula.

[腫瘤體積(mm3 )]=[腫瘤之長徑(mm)]×[腫瘤之短徑(mm)]2 ×0.5[Tumor volume (mm 3 )] = [long diameter of tumor (mm)] × [short diameter of tumor (mm)] 2 × 0.5

將被驗化合物投與開始日及投與終了日之溶劑群的腫瘤體積各為100%抑制及0%抑制並算出被驗化合物之抑制率。投與開始日起腫瘤體積若退縮時，投與開始日的腫瘤體積、及腫瘤消失的狀態各作為0%退縮及100%退縮並算出披驗化合物之退縮率。The tumor volume of the solvent group on the start date and the end of administration of the test compound was 100% inhibition and 0% inhibition, and the inhibition rate of the test compound was calculated. When the tumor volume is retracted from the start date, the tumor volume on the start of the administration and the state in which the tumor disappears are 0% retracted and 100% retracted, and the withdrawal rate of the test compound is calculated.

其結果於本發明化合物中，確認出抑制EML4-ALK融合蛋白質v1表現3T3細胞之腫瘤增殖的化合物，進一步確認可退縮EML4-ALK融合蛋白質v1表現3T3細胞之腫瘤的化合物之存在。對於幾個本發明化合物，抑制率如表3所示。但，表中記載「(退縮)」時，該數值表示退縮率。Ex表示實施例號碼。As a result, in the compound of the present invention, a compound which inhibits the tumor growth of the EML4-ALK fusion protein v1 exhibiting 3T3 cells was confirmed, and the presence of a compound in which the retractable EML4-ALK fusion protein v1 exhibits a tumor of 3T3 cells was further confirmed. For several compounds of the invention, the inhibition rates are shown in Table 3. However, when "(retraction)" is described in the table, the value indicates the withdrawal rate. Ex represents the embodiment number.

因此，藉由本發明化合物的經口投與，植入EML4-ALK融合蛋白質v1表現3T3細胞的老鼠之腫瘤增大受到抑制、或腫瘤經退縮，而確認本發明化合物具有經口投與之活性。Therefore, by the oral administration of the compound of the present invention, the tumor in which the EML4-ALK fusion protein v1 exhibits 3T3 cells is inhibited from being inhibited, or the tumor is retracted, and the compound of the present invention is confirmed to have an orally administered activity.

試驗例4對於EML4-ALK融合蛋白質依賴性細胞的抗腫瘤試驗(in vivo)Test Example 4 Anti-tumor test for EML4-ALK fusion protein-dependent cells (in vivo)

取代試驗例3的EML4-ALK融合蛋白質v1表現3T3細胞，使用人類非小細胞肺癌細胞株NCI-H2228細胞(來自EML4-ALK融合聚核苷酸陽性之肺癌患者的細胞(EML4-ALK融合蛋白質v3依賴性細胞))，如下述亦確認對於EML4-ALK融合蛋白質依賴性細胞的抗腫瘤效果。The EML4-ALK fusion protein v1 substituting test example 3 exhibited 3T3 cells, and human non-small cell lung cancer cell line NCI-H2228 cells (cells derived from EML4-ALK fusion polynucleotide-positive lung cancer patients (EML4-ALK fusion protein v3) were used. Dependent cells)), the anti-tumor effect on EML4-ALK fusion protein-dependent cells was also confirmed as follows.

將懸浮於50% MatrigeL(Invitrogen)的N CI-H2228細胞3×106 個注射於5週齡之雄性NOD/SCID老鼠(日本Charles River公司)的背部皮下而植入。植入3週後開始進行被驗化合物之投與。試驗以溶劑群及被驗化合物投與群各6匹進行，於10% 1-甲基-2-吡咯烷酮(SIGMA-ALDRICH公司)/90%聚乙二醇300(Fluka公司)的組成之溶劑中溶解於被驗化合物，將1 mg/kg進行經口投與。投與為14日間1天進行1次，體重及腫瘤徑為隔日進行測定。使用以下式子算出腫瘤體積。3 × 10 6 N CI-H2228 cells suspended in 50% Matrige L (Invitrogen) were injected subcutaneously into the back of a 5-week-old male NOD/SCID mouse (Charles River, Japan). The administration of the test compound was started 3 weeks after the implantation. The test was carried out in a solvent group and a test compound administered in groups of 6 in a solvent of 10% 1-methyl-2-pyrrolidone (SIGMA-ALDRICH) / 90% polyethylene glycol 300 (Fluka). Dissolved in the test compound and orally administered at 1 mg/kg. The administration was performed once a day for 14 days, and the body weight and tumor diameter were measured every other day. The tumor volume was calculated using the following formula.

[腫瘤體積(mm3 )]=[腫瘤的長徑(mm)]×[腫瘤的短徑(mm)]2 ×0.5[Tumor volume (mm 3 )] = [long diameter of tumor (mm)] × [short diameter of tumor (mm)] 2 × 0.5

將被驗化合物投與開始日及投與終了日之溶劑群的腫瘤體積各作為100%抑制及0%抑制，算出被驗化合物之抑制率。The tumor volume of the solvent group on the start of administration and the end of administration of the test compound was determined as 100% inhibition and 0% inhibition, and the inhibition rate of the test compound was calculated.

其結果，確認於本發明化合物中，存在抑制NCI-H2228細胞的腫瘤增殖之化合物。例如實施例549的化合物可將NCI-H2228細胞的腫瘤增殖抑制69%。As a result, it was confirmed that a compound which inhibits tumor growth of NCI-H2228 cells exists in the compound of the present invention. For example, the compound of Example 549 can inhibit tumor growth of NCI-H2228 cells by 69%.

因此，藉由本發明化合物的經口投與，植入人類非小細胞肺癌細胞株NCI-H2228細胞的老鼠中之腫瘤增大受到抑制，確認本發明化合物具有經口投與之活性。Therefore, by the oral administration of the compound of the present invention, tumor enlargement in a mouse implanted with human non-small cell lung cancer cell line NCI-H2228 cells was inhibited, and it was confirmed that the compound of the present invention has an orally administered activity.

另一方面，投與試驗例1所記載之Compound X及Compound Y時，與溶劑群比較，對於NCI-H2228細胞(腫瘤)並無顯著增殖抑制。且顯著差檢定係以Student's t檢定進行。On the other hand, when Compound X and Compound Y described in Test Example 1 were administered, there was no significant inhibition of proliferation of NCI-H2228 cells (tumor) as compared with the solvent group. Significant difference tests were performed with the Student's t test.

由以上結果確認本發明化合物於試驗例1～2中，具有EML4-ALK融合蛋白質之激酶活性的阻斷活性、具有EML4-ALK融合蛋白質依賴性細胞的增殖抑制活性。又，依據這些作用，試驗例3及試驗例4中，確認對於EML4-ALK融合蛋白質依賴性細胞(腫瘤)，具有抗腫瘤作用。由以上得知，本發明化合物可作為癌，作為某型態之肺癌、作為其他型態之非小細胞肺癌或小細胞肺癌、又作為其他型態之ALK融合聚核苷酸陽性之癌、進一步作為其他型態之ALK融合聚核苷酸陽性之肺癌、進一步作為其他型態之ALK融合聚核苷酸陽性的非小細胞肺癌、進一步作為其他型態之ALK融合蛋白質陽性的癌、進一步作為其他型態之ALK融合蛋白質陽性的肺癌、進一步作為其他型態之ALK融合蛋白質陽性的非小細胞肺癌、進一步作為其他型態之EML4-ALK融合聚核苷酸陽性的癌、進一步作為其他型態之EML4-ALK融合聚核苷酸陽性的肺癌、進一步作為其他型態之EML4-ALK融合聚核苷酸陽性的非小細胞肺癌、進一步作為其他型態之EML4-ALK融合蛋白質陽性的癌、進一步作為其他型態之EML4-ALK融合蛋白質陽性的肺癌、進一步作為其他型態之EML4-ALK融合蛋白質陽性的非小細胞肺癌等預防及/或治療用醫藥組成物之有效成分為有用。From the above results, it was confirmed that the compounds of the present invention have the blocking activity of the kinase activity of the EML4-ALK fusion protein and the proliferation inhibitory activity of the EML4-ALK fusion protein-dependent cells in Test Examples 1 and 2. Further, according to these effects, in Test Example 3 and Test Example 4, it was confirmed that the EML4-ALK fusion protein-dependent cells (tumor) have an antitumor effect. From the above, it is known that the compound of the present invention can be used as a cancer, as a certain type of lung cancer, as another type of non-small cell lung cancer or small cell lung cancer, and as another type of ALK fusion polynucleotide-positive cancer, further As another type of ALK fusion polynucleotide-positive lung cancer, further as another type of ALK fusion polynucleotide-positive non-small cell lung cancer, further as another type of ALK fusion protein-positive cancer, further as other The type of ALK fusion protein-positive lung cancer, further as another type of ALK fusion protein-positive non-small cell lung cancer, further as another type of EML4-ALK fusion polynucleotide-positive cancer, further as another type EML4-ALK fusion-nucleotide-positive lung cancer, further as another type of EML4-ALK fusion polynucleotide-positive non-small cell lung cancer, further as another type of EML4-ALK fusion protein-positive cancer, further as Other types of EML4-ALK fusion protein-positive lung cancer, further as other types of EML4-ALK fusion protein-positive non-small cells Cancer prevention and / or treatment with an active ingredient of pharmaceutical compositions useful.

又，有關至今的ALK基因，對於來自神經芽腫患者的細胞，已確認複數種類之活性型點變異的存在或基因增幅所引起的過剩表現(Nature,vol.455,p.971,2008；Cancer Research,vol.68,p.3389,2008)。又，具有ALK蛋白質的激酶活性之阻斷活性的化合物對於來自變異ALK聚核苷酸陽性的癌患者之細胞、或來自ALK聚核苷酸之過剩表現的癌患者之細胞，顯示抗腫瘤作用為已知(Cancer Research,vol.68,p.3389,2008)。由以上得知，可考慮本發明化合物可作為神經芽腫、作為某型態之變異ALK聚核苷酸陽性的癌、又作為其他型態之ALK聚核苷酸的過剩表現之癌、進一步作為其他型態之變異ALK聚核苷酸陽性的神經芽腫、進一步作為其他型態之ALK聚核苷酸的過剩表現之神經芽腫等預防及/或治療用醫藥組成物之有效成分為有用。Further, regarding the ALK gene to date, it has been confirmed that the presence of a plurality of types of active point mutations or the excessive expression caused by gene amplification for cells derived from patients with neuroblasts (Nature, vol. 455, p. 971, 2008; Cancer Research, vol. 68, p. 3389, 2008). Further, the compound having the blocking activity of the kinase activity of the ALK protein exhibits an antitumor effect against cells derived from a cancer patient having a positive ALK polynucleotide positive or a cancer patient having an excessive expression from an ALK polynucleotide. Known (Cancer Research, vol. 68, p. 3389, 2008). From the above, it can be considered that the compound of the present invention can be used as a neuroblast, a cancer which is positive for a certain type of ALK polynucleotide, and a cancer which is an excess of other types of ALK polynucleotides, and further Other types of variants of the ALK-nucleotide-positive neuroblasts are further useful as an active ingredient of a pharmaceutical composition for prevention and/or treatment of neuroblasts which are excessively expressed as other types of ALK polynucleotides.

又，將式(I)的化合物之藥理活性亦由以下試驗做確認。且，若無特別說明，以下所示試驗例可依據公知方法實施，使用販賣試藥或套組等時，可依據販賣品之說明書實施。Further, the pharmacological activity of the compound of the formula (I) was also confirmed by the following test. Further, unless otherwise specified, the test examples shown below can be carried out according to a known method, and when a test drug or a kit is sold, it can be carried out according to the instructions of the product.

試驗例5 RET蛋白質的激酶活性之阻斷活性評估Test Example 5 Evaluation of blocking activity of kinase activity of RET protein

僅RET蛋白質的激酶區域的部分蛋白質由Carna biosciences股份有限公司購得。對於肽基質之磷氧化活性使用EZreader(Caliper公司)進行檢討。將被驗化合物以最終濃度100 nM至0.03 nM的8階段與蛋白質溶液混合，其次添加ATP及基質肽(Caliper公司)混合液後進行30分鐘反應。ATP濃度作為100μM。製作出含有蛋白質而未添加被驗化合物的反應液(取代被驗化合物添加溶劑之僅DMSO 0.8%)，添加ATP、或未添加下進行相同反應。將在被驗化合物未添加之ATP未添加及添加時的磷氧化肽波峰各作為100%阻斷及0%阻斷，將50%阻斷時的被驗化合物濃度(IC50 )經邏輯回歸法算出。Only a portion of the protein of the kinase region of the RET protein was purchased from Carna Biosciences, Inc. The phosphating activity of the peptide matrix was reviewed using EZreader (Caliper). The test compound was mixed with the protein solution in an 8-stage final concentration of 100 nM to 0.03 nM, and a mixture of ATP and matrix peptide (Caliper) was added thereto, followed by a reaction for 30 minutes. The ATP concentration was taken as 100 μM. A reaction solution containing protein without adding a test compound (0.8% of DMSO in place of the test compound addition solvent) was prepared, and ATP was added or the same reaction was carried out without addition. The phosphorylated peptide peaks at the time when the ATP which was not added to the test compound was not added and added were each 100% blocked and 0% blocked, and the test compound concentration (IC 50 ) at 50% blocking was subjected to logistic regression. Calculated.

其結果，本發明化合物的幾個顯示對RET蛋白質之激酶活性具有阻斷活性。對於幾個本發明化合物，IC50 值如表4所示。Ex表示實施例號碼。As a result, several of the compounds of the present invention showed blocking activity against the kinase activity of the RET protein. For several compounds of the present invention, IC 50 values shown in Table 4. Ex represents the embodiment number.

RET(Rearranged during transfection)為受體型酪胺酸激酶，於中央部具有細胞膜貫通區域，於其羧基末端側具有酪胺酸激酶區域，於胺基末端側具有細胞外區域之蛋白質。RET (Rearranged during transfection) is a receptor-type tyrosine kinase having a cell membrane-penetrating region in the central portion, a tyrosine kinase region on the carboxyl terminal side, and an extracellular region protein on the amine terminal side.

由試驗例5的結果確認，本發明化合物具有RET蛋白質之激酶活性的阻斷活性。有關至今RET基因，對於來自非小細胞肺癌、小細胞肺癌、甲狀腺癌、副腎褐色細胞腫、大腸癌、及胰臟癌之細胞或癌組織檢體，確認活性型點變異，又對於來自甲狀腺癌、卵巢癌、及中皮腫的細胞或癌組織檢體，確認與H4、H4L、PRKAR1A、NCOA4、GOLGA5、HTIF1、TIF1G、TKTN1、RFG9、ELKS、PCM1、RFP、及HOOK3基因之融合(在非小細胞肺癌之點變異：Nature Genetics,2007,39,347-351；在小細胞肺癌之點變異：Japanese Journal of Cancer Research,1995,86,1127-1130；在甲狀腺癌之融合及點變異：Endocrine Reviews,2006,27,535-560；在副腎腫瘤之點變異：Journal of Clinical Endocrinology and Metabolism,1996,81,2041-2046；在大腸癌的點變異：Science,2006,314,268-274；在胰臟癌的點變異：Cancer Research,2005,65,11536-11544；在卵巢癌的融合：Internatinal Journal of Surgical Pathology,2009,17,107-110；在中皮腫之融合：Cancer letters,2008,265,55-66)。又，具有RET蛋白質之激酶活性的阻斷活性之化合物，對於來自變異RET聚核苷酸陽性之癌患者的細胞、來自融合型RET聚核苷酸陽性的癌患者之細胞顯示抗腫瘤作用為已知(Endocrine Reviews,2006,27,535-560)。由以上得知，本發明化合物可作為甲狀腺癌、作為某型態之副腎褐色細胞腫、又作為其他型態之大腸癌、進一步作為其他型態之胰臟癌、進一步作為其他型態之卵巢癌、進一步作為其他型態之中皮腫、進一步作為其他型態之變異RET聚核苷酸陽性之癌、進一步作為其他型態之變異RET聚核苷酸陽性的肺癌、進一步作為其他型態之變異RET聚核苷酸陽性的非小細胞肺癌、進一步作為其他型態之變異RET聚核苷酸陽性的小細胞肺癌、進一步作為其他型態之變異RET聚核苷酸陽性的甲狀腺癌、進一步作為其他型態之變異RET聚核苷酸陽性的副腎褐色細胞腫、進一步作為其他型態之變異RET聚核苷酸陽性的大腸癌、進一步作為其他型態之變異RET聚核苷酸陽性的胰臟癌、進一步作為其他型態之RET融合聚核苷酸陽性的癌、進一步作為其他型態之RET融合聚核苷酸陽性的甲狀腺癌、進一步作為其他型態之RET融合聚核苷酸陽性的卵巢癌、進一步作為其他型態之RET融合聚核苷酸陽性的中皮腫等預防及/或治療用醫藥組成物的有效成分亦為有用。From the results of Test Example 5, it was confirmed that the compound of the present invention has a blocking activity of the kinase activity of the RET protein. About the RET gene to date, for cells from non-small cell lung cancer, small cell lung cancer, thyroid cancer, paraneoplastic brown cell tumor, colorectal cancer, and pancreatic cancer, confirm the active point variation, and for thyroid cancer , ovarian cancer, and mesothelial cells or cancerous tissue samples, confirmed fusion with H4, H4L, PRKAR1A, NCOA4, GOLGA5, HTIF1, TIF1G, TKTN1, RFG9, ELKS, PCM1, RFP, and HOOK3 genes Point variation in small cell lung cancer: Nature Genetics, 2007, 39, 347-351; point variation in small cell lung cancer: Japanese Journal of Cancer Research, 1995, 86, 1127-1130; fusion and point mutation in thyroid cancer: Endocrine Reviews, 2006, 27, 535-560; Point variation in paraneoplastic tumors: Journal of Clinical Endocrinology and Metabolism, 1996, 81, 2041-2046; Point variation in colorectal cancer: Science, 2006, 314, 268-274; point variation in pancreatic cancer : Cancer Research, 2005, 65, 11536-11544; fusion in ovarian cancer: Internatinal Journal of Surgical Pathology, 2009, 17, 107-110; fusion in mesothelial swelling: Cancer letters, 2008, 265, 55-66). Further, a compound having a blocking activity of the kinase activity of the RET protein exhibits an antitumor effect on cells derived from a cancer patient having a positive RET polynucleotide positive, and a cancer patient derived from a fusion RET polynucleotide positive cancer patient. Known (Endocrine Reviews, 2006, 27, 535-560). From the above, it is known that the compound of the present invention can be used as thyroid cancer, as a type of paraneoplastic brown cell tumor, as another type of colorectal cancer, as another type of pancreatic cancer, and as another type of ovarian cancer. Further, as another type of cutaneous swelling, further as a variant of other types of RET-positive cancer, further as a variant of other types of RET-positive lung cancer, further as a variation of other forms Non-small cell lung cancer positive for RET polynucleotide, small cell lung cancer positive for other types of variant RET polynucleotides, further thyroid cancer positive for other types of variant RET polynucleotides, further as other Type of variant RET-nucleotide-positive accessory kidney brown cell tumor, further as another type of variant RET-nucleotide-positive colorectal cancer, further as another type of variant RET-nucleotide-positive pancreatic cancer Further, as another type of RET fusion polynucleotide-positive cancer, further as another type of RET fusion polynucleotide-positive thyroid cancer Further, it is useful as an active ingredient of a RET fusion polynucleotide-positive ovarian cancer of another type, and a medicinal composition for prevention and/or treatment such as a RET fusion polynucleotide positive for other types of RET fusion polynucleotides. .

試驗例6 ROS蛋白質的激酶活性之阻斷活性評估Test Example 6 Evaluation of blocking activity of kinase activity of ROS protein

僅將ROS蛋白質的激酶區域之部分蛋白質由Carna biosciences股份有限公司購得，實施與試驗例5之相同試驗。但，ATP及基質肽(Caliper公司)混合液中之ATP濃度為50uM。Only a part of the protein of the kinase region of the ROS protein was purchased from Carna Biosciences Co., Ltd., and the same test as in Test Example 5 was carried out. However, the ATP concentration in the mixture of ATP and matrix peptide (Caliper) was 50 uM.

其結果，本發明化合物的幾個顯示對ROS蛋白質之激酶活性具有阻斷活性。對於幾個本發明化合物，IC50 值如表5所示。Ex表示實施例號碼。As a result, several of the compounds of the present invention showed blocking activity against the kinase activity of the ROS protein. For several compounds of the present invention, IC 50 values as shown in Table 5. Ex represents the embodiment number.

ROS(v-Ros avian UR2 sarcoma virus oncogene homolog 1)為受體型酪胺酸激酶，於中央部具有細胞膜貫通區域，於羧基末端側具有酪胺酸激酶區域，於胺基末端側具有細胞外區域之蛋白質。ROS (v-Ros avian UR2 sarcoma virus oncogene homolog 1) is a receptor-type tyrosine kinase with a cell membrane-penetrating region at the central portion, a tyrosine kinase domain on the carboxy-terminal side, and an extracellular region on the amine-terminal side. Protein.

由試驗例6的結果確認本發明化合物為具有ROS蛋白質的激酶活性之阻斷活性者。有關至今ROS基因，對於來自非小細胞肺癌及膠芽腫之細胞或癌組織檢體，確認與FIG基因、SLC34A2基因、及CD74基因之融合(Biochimica et Biophysica Acta(BBA) Reviews on Cancer,2009,1795,37-52)。又，藉由已知對於來自SLC34A2-ROS融合聚核苷酸陽性的癌患者的細胞株，抑制該分子表現的siRNA為顯示抗腫瘤作用(Cell,2007,131,1190-1203)，具有ROS蛋白質的激酶活性之阻斷活性之化合物可期待對於ROS融合聚核苷酸陽性之癌顯示抗腫瘤作用。由以上得知本發明化合物可作為膠芽腫，作為某型態之ROS融合聚核苷酸陽性的癌、作為其他型態之ROS融合聚核苷酸陽性的肺癌、進一步作為其他型態之ROS融合聚核苷酸陽性的非小細胞肺癌、進一步作為其他型態之ROS融合聚核苷酸陽性的膠芽腫等預防及/或治療用醫藥組成物的有效成分為有用。From the results of Test Example 6, it was confirmed that the compound of the present invention is a blocking activity of the kinase activity of the ROS protein. Regarding the ROS gene to date, for cells derived from non-small cell lung cancer and glioblastoma or cancer tissue, fusion with the FIG gene, SLC34A2 gene, and CD74 gene was confirmed (Biochimica et Biophysica Acta (BBA) Reviews on Cancer, 2009, 1795, 37-52). Further, siRNA which inhibits the expression of the molecule is shown to exhibit an antitumor effect by a cell strain known to be a cancer patient positive from SLC34A2-ROS fusion polynucleotide (Cell, 2007, 131, 1190-1203), having ROS protein A compound which blocks the activity of kinase activity can be expected to exhibit an antitumor effect on a cancer positive for ROS fusion polynucleotide. From the above, it is known that the compound of the present invention can be used as a granuloma, as a certain type of ROS fusion polynucleotide-positive cancer, as another type of ROS fusion polynucleotide-positive lung cancer, and further as another type of ROS. It is useful for the non-small cell lung cancer which is positive for the fusion of the polynucleotide, and the active ingredient of the pharmaceutical composition for prevention and/or treatment such as a granuloma which is positive for other types of ROS fusion polynucleotides.

試驗例7 FLT3蛋白質的激酶活性之阻斷活性評估Test Example 7 Evaluation of blocking activity of kinase activity of FLT3 protein

僅將FLT3蛋白質的激酶區域之部分蛋白質由Carna biosciences股份有限公司購得，實施與試驗例5之相同試驗。Only a part of the protein of the kinase region of the FLT3 protein was purchased from Carna Biosciences Co., Ltd., and the same test as in Test Example 5 was carried out.

其結果，本發明化合物的幾個對於FLT3蛋白質之激酶活性顯示阻斷活性。對於幾個本發明化合物，IC50 值如表6所示。Ex表示實施例號碼。As a result, several of the compounds of the present invention showed blocking activity against the kinase activity of the FLT3 protein. For several compounds of the present invention, IC 50 values are shown in Table 6. Ex represents the embodiment number.

FLT3(Fms-like tyrosine kinase 3)為受體型酪胺酸激酶，於中央部具有細胞膜貫通區域，於其羧基末端側具有酪胺酸激酶區域，於胺基末端側具有細胞外區域之蛋白質。FLT3 (Fms-like tyrosine kinase 3) is a receptor-type tyrosine kinase having a cell membrane-penetrating region in the central portion, a tyrosine kinase region on the carboxyl terminal side, and an extracellular region protein on the amine terminal side.

由試驗例7的結果確認本發明化合物具有FLT3蛋白質的激酶活性之阻斷活性。有關至今FLT3基因，對於來自急性骨髓性白血病患者的細胞，確認活性型點變異及膜附近區域中之基因內縱列重複(Internal tandem duplication)變異(FLT3-ITD)，又對於來自異型慢性骨髓性白血病患者的細胞，確認與SPTBN1基因之融合(在急性骨髓性白血病之活性型點變異及在膜附近區域中之基因內縱列重複：Current Pharmaceutical Design,2005,11,3449-3457；在異型慢性骨髓性白血病之融合：Experimental Hematology,2007,35,1723-1727)。又，具有FLT3蛋白質的激酶活性之阻斷活性的化合物，對於來自變異FLT3聚核苷酸陽性的癌患者之細胞、或來自SPTBN1-FLT3融合聚核苷酸陽性的癌患者之細胞，顯示抗腫瘤作用為已知(Current Pharmaceutical Design,2005,11,3449-3457；Experimental Hematology,2007,35,1723-1727)。由以上得知，本發明化合物可作為急性骨髓性白血病，作為某型態之異型慢性骨髓性白血病患者、又作為其他型態之變異FLT3聚核苷酸陽性的癌、進一步作為其他型態之變異FLT3聚核苷酸陽性的急性骨髓性白血病、進一步作為其他型態之FLT3融合聚核苷酸陽性的癌、進一步作為其他型態之FLT3融合聚核苷酸陽性的異型慢性骨髓性白血病等預防及/或治療用醫藥組成物之有效成分亦為有用。From the results of Test Example 7, it was confirmed that the compound of the present invention has a blocking activity of the kinase activity of the FLT3 protein. With regard to the FLT3 gene to date, for cells derived from patients with acute myeloid leukemia, it is confirmed that the active point mutation and the intra-column repeat (Internal tandem duplication) variation (FLT3-ITD) in the vicinity of the membrane are also derived from the heterotopic chronic myelosuposis. The cells of leukemia patients were confirmed to be fused with the SPTBN1 gene (in the active point variation of acute myeloid leukemia and intra-column repeats in the vicinity of the membrane: Current Pharmaceutical Design, 2005, 11, 3449-3457; Fusion of myeloid leukemia: Experimental Hematology, 2007, 35, 1723-1727). Further, a compound having a blocking activity of a kinase activity of a FLT3 protein exhibits antitumor activity against cells derived from a cancer patient having a positive FLT3 polynucleotide-positive cancer or a cancer patient from a SPTBN1-FLT3 fusion polynucleotide-positive cancer patient The effect is known (Current Pharmaceutical Design, 2005, 11, 3449-3457; Experimental Hematology, 2007, 35, 1723-1727). From the above, it is known that the compound of the present invention can be used as an acute myeloid leukemia, as a type of heterozygous chronic myelogenous leukemia patient, and as another type of variant FLT3 polynucleotide-positive cancer, further as a variation of other forms. FLT3 polynucleotide-positive acute myeloid leukemia, further as another type of FLT3 fusion polynucleotide-positive cancer, further as another type of FLT3 fusion polynucleotide-positive heterologous chronic myelogenous leukemia prevention and the like / or the active ingredient of the therapeutic pharmaceutical composition is also useful.

試驗例8對於激酶阻斷分析被驗化合物，算出78種類的酪胺酸激酶(ABL、ARG、BTK、BMX、ITK、TEC、TXK、FRK、BLK、LCK、HCK、LYN、FGR、FYN、SRC、YES、BRK、SRM、CSK、CTK、FER、FES、ACK、TNK1、HER4、EGFR、HER2、JAK1、TYK2、JAK2、JAK3、ROS、ALK、LTK、IRR、INSR、IGF1R、DDR1、DDR2、MUSK、TRKA、TRKB、TRKC、TYRO3、AXL、MER、MET、RON、RET、FGFR4、FGFR1、FGFR2、FGFR3、FLT4、KDR、FLT1、FLT3、FMS、KIT、PDGFRα、PDGFRβ、TIE2、EphA1、EphA2、EphA8、EphA7、EphA6、EphA4、EphA3、EphA5、EphB4、EphB3、EphB1、EphB2、FAK、PYK2、SYK、ZAP70)在5nM的阻斷率。活性測定以Carna biosciences股份有限公司進行，作為數據解析方法，將含有所有反應組成之控制格的平均訊號作為0%阻斷，酵素非添加之平均訊號作為100%阻斷，由各被驗物質試驗2格之平均訊號計算出阻斷率。Test Example 8 For the kinase blocking analysis of the test compound, 78 types of tyrosine kinase (ABL, ARG, BTK, BMX, ITK, TEC, TXK, FRK, BLK, LCK, HCK, LYN, FGR, FYN, SRC) were calculated. , YES, BRK, SRM, CSK, CTK, FER, FES, ACK, TNK1, HER4, EGFR, HER2, JAK1, TYK2, JAK2, JAK3, ROS, ALK, LTK, IRR, INSR, IGF1R, DDR1, DDR2, MUSK , TRKA, TRKB, TRKC, TYRO3, AXL, MER, MET, RON, RET, FGFR4, FGFR1, FGFR2, FGFR3, FLT4, KDR, FLT1, FLT3, FMS, KIT, PDGFRα, PDGFRβ, TIE2, EphA1, EphA2, EphA8 Blocking rate of 5 nM, EphA7, EphA6, EphA4, EphA3, EphA5, EphB4, EphB3, EphB1, EphB2, FAK, PYK2, SYK, ZAP70). The activity was measured by Carna Biosciences Co., Ltd. As a data analysis method, the average signal of the control cells containing all reaction components was blocked as 0%, and the average signal of non-addition of enzymes was blocked as 100%, and the test substances were tested. The average signal of 2 grids calculates the blocking rate.

其結果對於5nM之濃度，由本發明之某化合物對於含有上述ALK、RET、ROS及FLT3之7種激酶僅顯示50%以上之阻斷活性得知，對於特定激酶之選擇性高，可考慮到造成副作用原因之標的以外的激酶阻斷所引起的安全性之顧慮較低。As a result, for a concentration of 5 nM, only one of the compounds of the present invention showed a blocking activity of 50% or more for the seven kinases containing the above ALK, RET, ROS, and FLT3, and the selectivity for a specific kinase was high, and it was considered that Concerns about the safety caused by kinase blockage other than the cause of side effects are low.

含有將式(I)的化合物或該製藥學上可被接受的鹽之1種或2種以上作為有效成分之醫藥組成物，可使用該領域中一般使用的藥劑用賦形劑、藥劑用載體等，可藉由一般使用的方法而調製。A pharmaceutical composition containing one or more of the compound of the formula (I) or the pharmaceutically acceptable salt as an active ingredient can be used as a pharmaceutical excipient or a pharmaceutical carrier which is generally used in the field. Etc., can be modulated by a method generally used.

投與可藉由錠劑、丸劑、膠囊劑、顆粒劑、散劑、液劑等進行經口投與、或關節內、靜脈內、肌肉內等注射劑、塞劑、點眼劑、眼軟膏、經皮用液劑、軟膏劑、經皮用貼劑、經黏膜液劑、經黏膜貼劑、吸入劑等非經口投與之任一形態亦可。Administration can be carried out by injectable tablets, pills, capsules, granules, powders, liquids, etc., or intra-articular, intravenous, intramuscular, etc., suppositories, eye drops, eye ointments, Any form of non-oral administration such as a skin solution, an ointment, a transdermal patch, a mucosal solution, a mucosal patch, or an inhalation may also be used.

作為使用於經口投與之固體組成物，使用錠劑、散劑、顆粒劑等。對於如此固體組成物，1種或2種以上的有效成分混合至少1種惰性賦形劑，例如混合乳糖、甘露糖醇、葡萄糖、羥基丙基纖維素、微結晶纖維素、澱粉、聚乙烯基吡咯烷酮、及/或甲基矽酸鋁酸鎂等。組成物可依據常法，亦可含有惰性添加劑，例如如硬脂酸鎂之滑澤劑或如羧基甲基澱粉鈉等崩壞劑、安定化劑、溶解補助劑。錠劑或丸劑可視必要以糖衣或胃溶性或腸溶性物質之薄膜包膜。As a solid composition for oral administration, a tablet, a powder, a granule, or the like is used. For such a solid composition, one or two or more active ingredients are mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl Pyrrolidone, and/or magnesium methyl phthalate. The composition may be according to a conventional method, and may also contain an inert additive such as a slip agent such as magnesium stearate or a breaker such as sodium carboxymethyl starch, a stabilizer, and a dissolution aid. Tablets or pills may optionally be coated with a film of sugar or gastric or enteric material.

使用於經口投與之液體組成物含有藥劑上可被接受的乳濁劑、溶液劑、懸浮劑、糖漿劑或酏劑等，含有一般使用的惰性稀釋劑，例如純化水或乙醇。該液體組成物亦可含有除惰性稀釋劑以外之如可溶化劑、濕潤劑、懸浮劑之補助劑、甜味劑、風味劑、芳香劑、防腐劑。The liquid composition for oral administration contains a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir, and the like, and contains an inert diluent which is generally used, such as purified water or ethanol. The liquid composition may also contain, in addition to an inert diluent, a solubilizing agent, a wetting agent, a suspending agent, a sweetener, a flavoring agent, a flavoring agent, and a preservative.

使用於非經口投與之注射劑為含有無菌水性或非水性之溶液劑、懸浮劑或乳濁劑。作為水性溶劑，例如含有注射用蒸餾水或生理食鹽液。作為非水性之溶劑，例如如丙二醇、聚乙二醇或橄欖油之植物油、如乙醇之醇類、或Polysorbate80(局方名)等。如此組成物亦可進一步含有等張化劑、防腐劑、濕潤劑、乳化劑、分散劑、安定化劑、或溶解補助劑。這些例如可藉由通過細菌保留濾器進行過濾、殺菌劑之添加或照射而使其無菌化。又，這些可在製造無菌之固體組成物時，於使用前溶解或懸浮於無菌水或無菌注射用溶劑中後使用。The injection for parenteral administration is a solution containing a sterile aqueous or nonaqueous solution, a suspending agent or an opacifying agent. The aqueous solvent contains, for example, distilled water for injection or physiological saline. As the nonaqueous solvent, for example, vegetable oil such as propylene glycol, polyethylene glycol or olive oil, alcohol such as ethanol, or Polysorbate 80 (office name) or the like. The composition may further contain an isotonic agent, a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer, or a dissolution aid. These can be sterilized, for example, by filtration through a bacteria retention filter, addition of bactericide or irradiation. Further, these can be used after dissolving or suspending in a sterile water or a sterile injectable solvent before use in the manufacture of a sterile solid composition.

作為外用劑，包含軟膏劑、硬膏劑、乳霜劑、凝膠劑、貼劑、噴霧劑、乳液劑、點眼劑、眼軟膏等。含有一般使用的軟膏基劑、乳液基劑、水性或非水性液劑、懸浮劑、乳劑等。例如作為軟膏或乳液基劑，可舉出聚乙二醇、丙二醇、白色凡士林、白蜜蠟、聚環氧乙烷硬化蓖麻油、單硬脂酸甘油、硬脂醇、鯨蠟醇、月桂聚乙二醇、半倍油酸山梨糖醇酐等。The external preparation includes an ointment, a plaster, a cream, a gel, a patch, a spray, an emulsion, an eye drop, an eye ointment, and the like. Contains commonly used ointment bases, emulsion bases, aqueous or non-aqueous liquids, suspensions, emulsions, and the like. For example, as an ointment or emulsion base, polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyethylene oxide hardened castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, and laurel Glycol, oleic acid sorbitan anhydride, and the like.

吸入劑或經鼻劑等經黏膜劑可使用固體、液體或半固體狀者，可依據過去公知方法製造。例如可適宜地添加公知賦形劑、或進一步添加pH調整劑、防腐劑、界面活性劑、滑澤劑、安定劑或增黏劑等。投與為可使用適當吸入或吹送的裝置。例如使用計量投與吸入裝置等公知裝置或噴霧器，可將化合物以單獨或作為經處方的混合物粉末、或與醫藥上可被接受的載體組合後作為溶液或懸浮液進行投與。乾燥粉末吸入器等亦可為單次或多次的使用於投與者，可利用含有乾燥粉末或粉末之膠囊。或亦可為使用適當驅出劑，例如氯氟鏈烷、氫氟鏈烷或二氧化碳等較佳氣體的加壓氣膠噴霧等形態。A solid, liquid or semi-solid can be used as the transmucosal agent such as an inhalant or a nasal spray, and can be produced according to a conventionally known method. For example, a known excipient or a pH adjuster, a preservative, a surfactant, a slip agent, a stabilizer or a tackifier may be added as appropriate. The device is administered as a device that can be properly inhaled or blown. For example, the compound can be administered as a solution or suspension, either alone or as a prescribed mixture powder, or in combination with a pharmaceutically acceptable carrier, using a known device such as a metered administration inhalation device or a nebulizer. The dry powder inhaler or the like may be used in a single or multiple times for administration, and a capsule containing a dry powder or powder may be used. Alternatively, it may be in the form of a pressurized gas mist spray using a suitable expelling agent such as a chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.

一般進行經口投與時，1日的投與量對體重而言約0.001~100 mg/kg、較佳為0.005~30 mg/kg，更佳為0.01~10 mg/kg，將此分為1次或2至4次進行投與。進行靜脈內投與時，1日的投與量對於體重而言約0.0001~10 mg/kg，分為1天1次至複數次進行投與。又，作為經黏膜劑，對於體重而言約0.001~100 mg/kg，分為1日1次至複數次進行投與。投與量可考慮到症狀、年齡、性別等配合各情況而適宜決定。Generally, when administered orally, the dose on the 1st is about 0.001 to 100 mg/kg, preferably 0.005 to 30 mg/kg, more preferably 0.01 to 10 mg/kg, based on the body weight. 1 or 2 to 4 times for administration. In the case of intravenous administration, the administration amount per day is about 0.0001 to 10 mg/kg for the body weight, and is administered once a day to a plurality of times. Further, the transmucosal agent is administered in an amount of about 0.001 to 100 mg/kg for the body weight, and is administered once a day to a plurality of times. The amount of administration can be appropriately determined in consideration of the symptoms, age, sex, etc. in accordance with each situation.

式(I)的化合物可與被認為前述式(I)的化合物顯示有效性的疾病之種種治療劑或預防劑併用。一般而言，對於腫瘤，特別對於惡性腫瘤的化療法，單獨投與抗腫瘤劑時，由副作用等觀點來看該效果有極限，大多無法得到充分的抗腫瘤效果。因此，臨床時進行組合作用機制相異的2劑或3劑以上的多劑併用療法。該併用療法為藉由組合作用機制相異的抗腫瘤劑係以1)可減少非感受性細胞集團、2)預防或遲延藥劑耐性出現、3)毒性相異的藥劑之組合可分散毒性等副作用的減輕或抗腫瘤作用之增強作為目的。該併用可同時投與、或連續各別、或以所望時間間隔下進行投與。同時投與製劑可為配合劑或各別地製劑化者。The compound of the formula (I) can be used in combination with various therapeutic or prophylactic agents for diseases which are considered to be effective for the compound of the above formula (I). In general, when an antitumor agent is administered alone to a tumor, particularly for the chemotherapy of a malignant tumor, the effect is limited from the viewpoint of side effects and the like, and a sufficient antitumor effect is often not obtained. Therefore, two or more than three doses of a combination of different mechanisms of action are used in combination in the clinic. The combined therapy is an antitumor agent which differs by a combination of action mechanisms: 1) can reduce non-sensitive cell groups, 2) prevent or delay the occurrence of drug resistance, 3) a combination of agents having different toxicity, dispersible toxicity and the like. The purpose of reducing or enhancing the anti-tumor effect is for the purpose. The combined use can be administered simultaneously, or continuously, or at desired intervals. Simultaneous administration of the preparation may be a compounding agent or a separate formulation.

作為可併用之藥劑，可舉出烷基化劑、代謝拮抗劑等化療法劑、免疫療法劑、賀爾蒙療法劑、細胞增殖因子阻斷劑，具體可舉出順鉑(Cisplatin)、卡鉑(Carboplatin)、紫杉醇(Paclitaxel)、多烯紫杉醇(Docetaxel)、吉西他濱(Gemcitabine)、愛萊諾迪肯(Irinotecan)、溫諾平(Vinorelbine)、癌思停(Bevacizumab)、愛寧達(Pemetrexed)等藥劑。Examples of the pharmaceutically acceptable agent include a chemotherapeutic agent such as an alkylating agent or a metabolic antagonist, an immunotherapy agent, a hormone therapy agent, and a cell proliferation factor blocker, and specific examples thereof include Cisplatin and a card. Carboplatin, Paclitaxel, Docetaxel, Gemcitabine, Irinotecan, Vinorelbine, Bevacizumab, Pemetrexed ) and other drugs.

[實施例][Examples]

以下依據實施例，更詳細說明式(I)之化合物的製造法。且，本發明並未限定於下述實施例所記載之化合物。又，將原料化合物之製法以各製造例表示。又，式(I)的化合物之製造法並未僅限定於以下所示具體實施例之製造法，式(I)的化合物可由這些製造法之組合、或藉由斯業者熟知的方法製造而得。Hereinafter, the production method of the compound of the formula (I) will be explained in more detail based on the examples. Further, the present invention is not limited to the compounds described in the following examples. Moreover, the manufacturing method of a raw material compound is shown by each manufacturing example. Further, the production method of the compound of the formula (I) is not limited to the production method of the specific examples shown below, and the compound of the formula (I) can be produced by a combination of these production methods or by a method known to the manufacturer. .

又，對於實施例、製造例及後述表中，有時使用以下簡稱。Further, in the examples, the production examples, and the tables to be described later, the following abbreviations may be used.

Rex：製造例號碼、Ex：實施例號碼、Structure：化學結構式、Data：物理化學的數據(FAB+：FAB-MS[M+H]+ 、ESI+：ESI-MS[M+H]+ 、APCI/ESI+：APCI/ESI-MS[M+H]+ (APCI/ESI表示APCI與ESI之同時測定)、FAB-：FAB-MS[M-H]- 、ESI-：ESI-MS[M-H]- 、APCI-：APCI-MS[M-H]- 、1 H-NMR(CDCl3)：重氯仿中之1 H-NMR中波峰之δ(ppm)、1 H-NMR(CD3OD)：重甲醇中之1 H-NMR中波峰之δ(ppm)、1 H-NMR(CDCl3+CD3OD)：重氯仿及重甲醇混液中之1 H-NMR中波峰的δ(ppm)、1 H-NMR(DMSO-d6)：DMSO-d6 中之1 H-NMR中波峰之δ(ppm)、XRD：粉末X線繞射測定中主要波峰之繞射角2θ(°))、HCl：表示作為鹽酸鹽而得者、2HCl：表示作為2鹽酸鹽而得者、TsOH：表示作為p-甲苯磺酸鹽而得者、HFM：表示作為半富馬酸鹽而得者、FM：表示作為富馬酸鹽而得者、Me：甲基、Et：乙基、nPr：正丙基、iPr：異丙基、cPr：環丙基、cHex：環己基、Ph：苯基、Bn：苯甲基、Boc：tert-丁氧基羰基、Ac：乙醯基。Syn：製造方法(表示該化合物藉由與如表所述製造例或實施例之相同方法，使用對應原料而製造)。且，對於製造例或實施例之表中，存在順式-反式異構物，雖該立體配置尚未決定，但對於表示順式或反式之任一方單一立體配置的化合物，並未表示在化學結構式中之立體配置，於製造例號碼或實施例號碼附上*。又，*後附上相同數字之化合物表示一方為順式體、另一方為反式體。Rex: manufacturing example number, Ex: example number, Structure: chemical structural formula, Data: physical chemical data (FAB+: FAB-MS [M+H] + , ESI+: ESI-MS [M+H] + , APCI /ESI+: APCI/ESI-MS[M+H] + (APCI/ESI indicates simultaneous measurement of APCI and ESI), FAB-: FAB-MS [MH] - , ESI-: ESI-MS [MH] - , APCI -: APCI-MS [MH] - , 1 H-NMR (CDCl3): δ (ppm) of peak in 1 H-NMR in heavy chloroform, 1 H-NMR (CD3OD): 1 H-NMR in heavy methanol δ (ppm), 1 H-NMR (CDCl3 + CD3 OD) of the middle peak: δ (ppm), 1 H-NMR (DMSO-d6): DMSO- in the peak of 1 H-NMR in heavy chloroform and heavy methanol mixture δ (ppm) of the peak in 1 H-NMR in d 6 , XRD: diffraction angle 2θ (°) of the main peak in the powder X-ray diffraction measurement, HCl: represents the hydrochloride as a salt, 2 HCl: The product represented by the two hydrochlorides, TsOH: which is obtained as p-toluenesulfonate, HFM: which is obtained as a hemi-fumarate, and FM: which is obtained as a fumarate, Me : methyl, Et: ethyl, nPr: n-propyl, iPr: isopropyl, cPr: cyclopropyl, cHex: cyclohexyl, Ph: phenyl, Bn: benzyl, Boc: tert-butyl Carbonyl group, Ac: acetyl group. Syn: Manufacturing method (indicating that the compound is produced by using the corresponding raw materials by the same method as the production example or the examples described in the Table). Further, in the tables of the production examples or the examples, the cis-trans isomer is present, and although the stereo configuration has not been determined, it is not indicated for the compound indicating a single stereo configuration of either cis or trans. The stereo configuration in the chemical structure is attached to the manufacturing example number or the embodiment number*. Further, a compound having the same number appended to * indicates that one is a cis-form and the other is a trans-form.

又，粉末X線繞射之測定使用RINT-TTR II，在管球：Cu、管電流：300 mA、管電壓：50 kV、取樣幅：0.020°、走査速度：4°/min、波長：1.54056、測定繞射角範圍(2θ)：2.5～40°之條件下進行測定。且，粉末X線繞射對於數據性質上、結晶之相同性認定上，結晶格子間隔或全體圖型為重要依據，相對強度則會藉由結晶成長之方向、粒子大小、測定條件而多多少少有改變，故應無須嚴密地解讀。In addition, the powder X-ray diffraction was measured using RINT-TTR II, in the tube ball: Cu, tube current: 300 mA, tube voltage: 50 kV, sampling width: 0.020°, walking speed: 4°/min, wavelength: 1.54056 The measurement was carried out under the conditions of measuring the diffraction angle range (2θ): 2.5 to 40°. Moreover, the powder X-ray diffraction is important for the nature of the data and the identity of the crystal. The crystal lattice spacing or the overall pattern is an important basis, and the relative intensity is more or less by the direction of crystal growth, particle size, and measurement conditions. There are changes, so there should be no need to interpret them closely.

製造例4Manufacturing Example 4

將4-甲基-3-硝基安息香酸(1.97 g)與氯化亞碸(6 mL)之混合物進行18小時加熱迴流。將反應液經減壓濃縮後，與甲苯共沸，得到紅褐色油狀物。於此與THF(25 mL)之混合物中，冰冷下加入二乙基胺(2.6 mL)，在室溫進行5小時攪拌。將反應液注入水中，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥，將溶劑減壓餾去後得到N,N-二乙基-4-甲基-3-硝基苯甲醯胺(2.61 g)之褐色油狀物。A mixture of 4-methyl-3-nitrobenzoic acid (1.97 g) and hydrazine chloride (6 mL) was heated to reflux for 18 hours. The reaction mixture was concentrated under reduced pressure and then evaporated toluene toluene. To a mixture of THF (25 mL), diethylamine (2.6 mL) was then evaporated. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Brown oil.

製造例41Manufacturing Example 41

於2-甲氧基-4-硝基苯磺醯基氯化物(600 mg)與THF(5 mL)之混合物中，加入哌啶(406 mg)與THF(1 mL)之混合物，在室溫下進行12小時攪拌。於反應液加入10%鹽酸後，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥，將溶劑減壓餾去後得到1-[(2-甲氧基-4-硝基苯基)磺醯基]哌啶(714 mg)之黃色固體。To a mixture of 2-methoxy-4-nitrophenylsulfonyl chloride (600 mg) in THF (5 mL), a mixture of piperidine (406 mg) and THF (1 mL) Stir for 12 hours. After adding 10% hydrochloric acid to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and then evaporated to dryness to give 1-[(2-methoxy-4-nitrophenyl)sulfonyl]piperidine (714). Mg) of a yellow solid.

製造例48Manufacturing Example 48

將2-氟-5-硝基安息香酸(600 mg)與氯化亞碸(2 mL)之混合物，進行15小時加熱迴流。將反應液經減壓濃縮後，與甲苯共沸得到黃色結晶。於此與THF(11 mL)之混合物中，冰冷下加入三乙胺(0.47 mL)及異丙基胺(0.29 mL)，在室溫進行5小時攪拌。將反應液注入水中，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥，將溶劑減壓餾去後得到黃色結晶。於該黃色結晶(723 mg)、甲醇(8 mL)與水(3 mL)之混合物中，加入氯化銨(2.05 g)、鋅粉末(2.09 g)，進行3小時加熱迴流。將反應懸浮液經矽藻石過濾後，將濾液經減壓濃縮。將殘渣注入於飽和碳酸氫鈉水溶液中，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥，將溶劑經減壓餾去。將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇)進行純化後得到5-胺基-2-氟-N-異丙基苯甲醯胺(527 mg)之淡褐色結晶。A mixture of 2-fluoro-5-nitrobenzoic acid (600 mg) and hydrazine chloride (2 mL) was heated and refluxed for 15 hours. The reaction solution was concentrated under reduced pressure and then aq. To a mixture of THF (11 mL), triethylamine (0.47 mL) and isopropylamine (0.29 mL) The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Ammonium chloride (2.05 g) and zinc powder (2.09 g) were added to a mixture of the yellow crystals (723 mg), methanol (8 mL) and water (3 mL), and the mixture was heated to reflux for 3 hours. After the reaction suspension was filtered through celite, the filtrate was concentrated under reduced pressure. The residue was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (yield: chloroform:methanol) to give 5-amino-2-fluoro-N-isopropylbenzamide (527 mg) as pale brown crystals.

製造例160Manufacturing Example 160

於3,5-二氯-6-乙基吡嗪-2-甲醯胺(1.0 g)與DMF(15 mL)的混合物中，在室溫加入氯化亞碸(1 mL)進行20分鐘攪拌。將反應液注入於冰水中，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥，將溶劑經減壓餾去。將殘渣於矽膠管柱層析法(溶離液；乙酸乙酯：n-己烷)進行純化後得到3,5-二氯-6-乙基吡嗪-2-腈(608 mg)之微黃色油狀物。In a mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (1.0 g) and DMF (15 mL), add hydrazine chloride (1 mL) at room temperature for 20 min. . The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (solvent; ethyl acetate: n-hexane) to give 3,5-dichloro-6-ethylpyrazine-2-carbonitrile (608 mg). Oily.

製造例194Manufacturing Example 194

於甲基5-氯-3-{[4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-羧酸酯(製造例193)(20 mg)與THF(2mL)的混合物之溶液中加入O-甲基羥胺鹽酸鹽(14 mg)。於反應液，冰冷下加入LHMDS(lithium hexamethyldisilazide)(0.39 mL,1M THF溶液)，進行20分鐘攪拌。將反應液注入於飽和碳酸氫鈉水溶液，以乙酸乙酯萃取後，將有機層以飽和食鹽水洗淨。以無水硫酸鈉乾燥後，將溶劑減壓餾去後得到5-氯-N-甲氧基-3-{[4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺(21 mg)之黃色粉末。Methyl 5-chloro-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxylate (Production Example 193) (20 mg) and THF To a solution of the (2 mL) mixture was added O-methylhydroxylamine hydrochloride (14 mg). LHMDS (lithium hexamethyldisilazide) (0.39 mL, 1 M THF solution) was added to the reaction mixture under ice cooling, and the mixture was stirred for 20 minutes. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate, and the organic layer was washed with brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give 5-chloro-N-methoxy-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino} Yellow powder of pyrazin-2-carboxamide (21 mg).

製造例240Manufacturing Example 240

於1-(2-碘-4-硝基苯基)-4-甲基哌嗪(製造例241)(406 mg)、甲苯(3 mL)與水(3 mL)的混合物中，氬氣環境下加入碳酸鈉(496 mg)、苯基硼酸(157 mg)、肆(三苯基膦)鈀(68 mg)，在110 ℃進行一晚攪拌。將反應液注入於水中，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥，將溶劑經減壓餾去。將殘渣於矽膠管柱層析法(溶離液；氯仿/甲醇)進行純化後得到1-甲基-4-(5-硝基聯苯基-2-基)哌嗪(348 mg)之黃褐色油狀物。Argon atmosphere in a mixture of 1-(2-iodo-4-nitrophenyl)-4-methylpiperazine (manufacturing example 241) (406 mg), toluene (3 mL) and water (3 mL) Sodium carbonate (496 mg), phenylboronic acid (157 mg), hydrazine (triphenylphosphine) palladium (68 mg) were added, and stirred at 110 ° C overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (solvent; chloroform/methanol) to give 1-methyl-4-(5-nitrobiphenyl-2-yl)piperazine (348 mg) as a tan. Oily.

製造例244Manufacturing example 244

於N-[2-(4-甲基哌嗪-1-基)-5-硝基苯基]乙醯胺(433 mg)與DMF(5 mL)的混合物，冰冷下加入63%油性氫化鈉(66 mg)，在室溫進行1小時攪拌。將反應液再次冰冷下，加入碘化甲基(0.11 mL)，在室溫進行4小時攪拌。將反應液注入於飽和氯化銨水溶液，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥，將溶劑經減壓餾去。將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇)進行純化後得到N-甲基-N-[2-(4-甲基哌嗪-1-基)-5-硝基苯基]乙醯胺(200 mg)之橙色固體。a mixture of N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]acetamide (433 mg) and DMF (5 mL). (66 mg), stirring at room temperature for 1 hour. The reaction solution was again ice-cooled, and methyl iodide (0.11 mL) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (solvent; chloroform:methanol) to give N-methyl-N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl An orange solid of acetaminophen (200 mg).

製造例246Manufacturing Example 246

於tert-丁基(4-側氧基環己基)胺甲酸酯(3.04 g)與THF(100 mL)的混合物，在-78℃加入乙基鋰(0.5M苯-環己烷溶液)(56.8 mL)，經4小時攪拌至-50℃。於反應液加入水(150 mL)，昇溫至室溫，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後，以硫酸鈉乾燥，將溶劑餾去。將所得之殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇=30：1)，並進一步以(溶離液；n-己烷：乙酸乙酯=2：1-1：1)純化，得到低極性生成物之tert-丁基(4-乙基-4-羥基環己基)胺甲酸酯(製造例246)(0.202 g)的白色固體、及高極性生成物之tert-丁基(4-乙基-4-羥基環己基)胺甲酸酯(製造例248)的無色糖漿狀物。A mixture of tert-butyl(4-oxocyclohexyl)carbamate (3.04 g) and THF (100 mL) was added at -78 ° C to ethyl lithium (0.5 M benzene-cyclohexane) 56.8 mL), stirred to -50 ° C over 4 hours. Water (150 mL) was added to the reaction mixture, and the mixture was evaporated. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated. The obtained residue was purified by column chromatography (solvent; chloroform:methanol = 30:1), and further purified (solvent; n-hexane: ethyl acetate = 2:1 to 1:1). A tert-butyl(4-ethyl-4-hydroxycyclohexyl)carbamate of low polarity product (Production Example 246) (0.202 g) as a white solid and a tert-butyl group of a highly polar product were obtained. A colorless syrup of 4-ethyl-4-hydroxycyclohexyl)carbamate (Production Example 248).

製造例247Manufacturing Example 247

於tert-丁基(4-乙基-4-羥基環己基)胺甲酸酯(製造例246)(0.202 g)與二噁烷(2 mL)的混合物，冰冷下加入26%氯化氫-二噁烷(1.1 mL)，在室溫進行12小時攪拌。將溶劑餾去後得到4-胺基-1-乙基環己醇鹽酸鹽(0.140 g)之白色黏性固體。a mixture of tert-butyl(4-ethyl-4-hydroxycyclohexyl)carbamate (manufacturing example 246) (0.202 g) and dioxane (2 mL), 26% hydrogen chloride-dioxin under ice cooling The alkane (1.1 mL) was stirred at room temperature for 12 hours. The solvent was distilled off to give 4-amino-1-ethylcyclohexanol hydrochloride (0.140 g) as a white solid.

製造例249Manufacturing Example 249

於tert-丁基(4-乙基-4-羥基環己基)胺甲酸酯(製造例248)(0.256 g)與二噁烷(2 mL)的混合物，冰冷下加入26%氯化氫-二噁烷(1.4 mL)，在室溫進行17小時攪拌。將析出固體經濾取後得到4-胺基-1-乙基環己醇鹽酸鹽(0.152 g)之白色固體。a mixture of tert-butyl(4-ethyl-4-hydroxycyclohexyl)carbamate (manufacturing example 248) (0.256 g) and dioxane (2 mL), 26% hydrogen chloride-dioxin under ice cooling The alkane (1.4 mL) was stirred at room temperature for 17 hours. The precipitated solid was filtered to give 4-amino-1-ethylcyclohexanol hydrochloride (0.152 g) as a white solid.

製造例250Manufacturing Example 250

於tert-丁基(4-側氧基環己基)胺甲酸酯(3.04 g)與THF(100 mL)的混合物，在-78℃加入異丙基鋰(0.7M戊烷溶液)(40.3 mL)，經4小時攪拌至-50℃。於反應液加入水(150 mL)，昇溫至室溫，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨後，以硫酸鈉乾燥，將溶劑餾去。將所得之殘渣於矽膠管柱層析法(溶離液；n-己烷：乙酸乙酯=3：1)，並進一步以(溶離液；氯仿：甲醇=30：1)進行純化，得到低極性生成物之tert-丁基(4-異丙基-4-羥基環己基)胺甲酸酯(製造例250)(0.854 g)的白色固體、及高極性生成物之tert-丁基(4-異丙基-4-羥基環己基)胺甲酸酯(製造例252)(0.179 g)的黃色油狀物。a mixture of tert-butyl(4-oxocyclohexyl)carbamate (3.04 g) and THF (100 mL), isopropyl lithium (0.7 M in pentane) (40.3 mL) at -78 °C ), stirred to -50 ° C over 4 hours. Water (150 mL) was added to the reaction mixture, and the mixture was evaporated. The organic layer was washed with saturated brine, dried over sodium sulfate and evaporated. The obtained residue was subjected to silica gel column chromatography (eluting solution; n-hexane: ethyl acetate = 3:1), and further purified by (solvent; chloroform:methanol = 30:1) to obtain low polarity. The product was obtained as a white solid of tert-butyl(4-isopropyl-4-hydroxycyclohexyl)carbamate (manufacturing example 250) (0.854 g) and a highly polar product of tert-butyl (4- Isopropyl-4-hydroxycyclohexyl)carbamate (manufacturing example 252) (0.179 g) as a yellow oil.

製造例251Manufacturing Example 251

於tert-丁基(4-異丙基-4-羥基環己基)胺甲酸酯(製造例250)(0.392 g)與二噁烷(3 mL)的混合物中，冰冷下加入26%氯化氫-二噁烷(2.0 mL)，在室溫進行18小時攪拌。將析出之固體濾取後得到4-胺基-1-異丙基環己醇鹽酸鹽(0.190 g)之白色固體。In a mixture of tert-butyl(4-isopropyl-4-hydroxycyclohexyl)carbamate (manufacturing example 250) (0.392 g) and dioxane (3 mL), 26% hydrogen chloride was added under ice cooling - Dioxane (2.0 mL) was stirred at room temperature for 18 hours. The precipitated solid was filtered to give 4-amino-1-isopropylcyclohexanol hydrochloride (0.190 g) as a white solid.

製造例253Manufacturing Example 253

於tert-丁基(4-異丙基-4-羥基環己基)胺甲酸酯(製造例252)(0.179 g)與二噁烷(1.5 mL)的混合物中，冰冷下加入26%氯化氫-二噁烷(0.9 mL)，在室溫進行18小時攪拌。將析出之固體經濾取後得到4-胺基-1-異丙基環己醇鹽酸鹽(0.086 g)之白色固體。In a mixture of tert-butyl(4-isopropyl-4-hydroxycyclohexyl)carbamate (manufacturing example 252) (0.179 g) and dioxane (1.5 mL), 26% hydrogen chloride was added under ice cooling - Dioxane (0.9 mL) was stirred at room temperature for 18 hours. The precipitated solid was filtered to give 4-amino-1-isopropylcyclohexanol hydrochloride (0.086 g) as a white solid.

製造例287Manufacturing Example 287

於丙烷-2-硫醇基(3.30 mL)、碳酸鉀(6.60 g)及DMF(40 mL)的混合物中，加入1-氟-4-甲基-2-硝基苯(4.85 g)，在室溫進行5小時攪拌。於反應液加入水，並以乙酸乙酯萃取，將萃取液以水及飽和食鹽水洗淨。以無水硫酸鈉乾燥後，將溶劑進行減壓餾去後得到1-(異丙基磺醯基)-4-甲基-2-硝基苯(6.60 g)之黃色油狀物。Add 1-fluoro-4-methyl-2-nitrobenzene (4.85 g) to a mixture of propane-2-thiol (3.30 mL), potassium carbonate (6.60 g) and DMF (40 mL) Stirring was carried out for 5 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated.

製造例291Manufacturing Example 291

於1-(異丙基磺醯基)-4-甲基-2-硝基苯(製造例287)(6.60 g)與氯仿(150 mL)的混合物中，加入m-氯過安息香酸(18.0 g)，在50℃進行12小時攪拌。將反應液冷卻後，加入飽和碳酸氫鈉水溶液及5%亞硫酸鈉水溶液，以氯仿萃取。將有機層以無水硫酸鈉乾燥後，將溶劑進行減壓餾去後得到2-(異丙基磺醯基)-4-甲基-1-硝基苯(7.41 g)之黃色固體。M-chloroperbenzoic acid (18.0) was added to a mixture of 1-(isopropylsulfonyl)-4-methyl-2-nitrobenzene (Production Example 287) (6.60 g) and chloroform (150 mL). g), stirring at 50 ° C for 12 hours. After cooling the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate and a 5% aqueous sodium The organic layer was dried over anhydrous sodium sulfate.

製造例292Manufacturing Example 292

於2-(異丙基磺醯基)-4-甲基-1-硝基苯(製造例291)(7.41 g)與乙酸(70 mL)的混合物中，加入鐵粉(5.43 g)，在80℃進行3小時攪拌後，除去反應液之不溶物並將溶劑經減壓餾去。於殘渣加入乙酸乙酯(150 mL)除去不溶物後，以水及飽和食鹽水洗淨。以無水硫酸鈉乾燥後，將溶劑經減壓餾去。將殘渣以乙酸乙酯-二異丙醚洗淨後得到2-(異丙基磺醯基)-4-甲基苯胺(3.86 g)之淡黃色固體。Iron powder (5.43 g) was added to a mixture of 2-(isopropylsulfonyl)-4-methyl-1-nitrobenzene (Production Example 291) (7.41 g) and acetic acid (70 mL). After stirring at 80 ° C for 3 hours, the insoluble matter of the reaction liquid was removed and the solvent was distilled off under reduced pressure. Ethyl acetate (150 mL) was added to the residue to remove insoluble materials, and then washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate-diisopropyl ether to give 2-(isopropylsulfonyl)-4-methylaniline (3.86 g).

製造例298Manufacturing Example 298

於55%油性氫化鈉(733 mg)與DMF(20 mL)的混合物中，冰冷下加入3-(甲基磺醯基)苯胺(1.44 g)與THF(20 mL)的混合物，在冰冷進行30分鐘攪拌。於反應液中，將4,6-二氯-2-(甲基磺醯基)嘧啶-5-甲醯胺(2.0 g)與DMF(30 mL)的混合物經15分鐘滴入，並在冰冷下進行15分鐘攪拌。加入10%檸檬酸水溶液(300 mL)，以乙酸乙酯萃取後，將有機層以飽和食鹽水洗淨。以無水硫酸鎂乾燥後，溶劑經濃縮，將析出之固體經濾取、乾燥後得到4-氯-2-(甲基磺醯基)-6-{[3-(甲基磺醯基)苯基]胺基}嘧啶-5-甲醯胺(1.95 g)之淡黃色固體。A mixture of 5-(methylsulfonyl)aniline (1.44 g) and THF (20 mL) was added to a mixture of 55% aqueous sodium hydride (733 mg) and DMF (20 mL). Stir in minutes. In a reaction mixture, a mixture of 4,6-dichloro-2-(methylsulfonyl)pyrimidine-5-carboxamide (2.0 g) and DMF (30 mL) was added dropwise over 15 min. Stir for 15 minutes. After adding a 10% aqueous citric acid solution (300 mL) and extracting with ethyl acetate, the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent is concentrated, and the precipitated solid is filtered and dried to give 4-chloro-2-(methylsulfonyl)-6-{[3-(methylsulfonyl)benzene. A pale yellow solid of amino]pyrimidine-5-carbamide (1.95 g).

製造例299Manufacturing Example 299

於4-氯-2-(甲基磺醯基)-6-{[3-(甲基磺醯基)苯基]胺基}嘧啶-5-甲醯胺(製造例298)(1.95 g)與DMSO(30 mL)的混合物中，加入碳酸鉀(1.81 g)及30%過氧化氫水(2.65 mL)，在50℃進行1.5小時攪拌。將反應液冰冷後加入1M鹽酸(25 mL)，繼續加入水(150 mL)，直接進行30分鐘攪拌。將析出之固體經濾取並以水洗淨後得到2-(甲基磺醯基)-4-{[3-(甲基磺醯基)苯基]胺基}-6-側氧基-1,6-二氫嘧啶-5-甲醯胺(1.40 g)之淡黃色固體。4-Chloro-2-(methylsulfonyl)-6-{[3-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxamide (Production Example 298) (1.95 g) Potassium carbonate (1.81 g) and 30% hydrogen peroxide water (2.65 mL) were added to a mixture with DMSO (30 mL), and stirred at 50 ° C for 1.5 hours. After the reaction mixture was ice-cooled, 1M hydrochloric acid (25 mL) was added, and water (150 mL) was further added and the mixture was stirred for 30 minutes. The precipitated solid was filtered and washed with water to give 2-(methylsulfonyl)-4-{[3-(methylsulfonyl)phenyl]amino}-6-sideoxy- 1,6-Dihydropyrimidine-5-carboxamide (1.40 g) as a pale yellow solid.

製造例304Manufacturing Example 304

於4-氯-6-[(6-甲基吡啶-3-基)胺基]-2-(甲基磺醯基)嘧啶-5-甲醯胺(製造例303)(51 mg)與甲醇(1 mL)的混合物中，冰冷下加入甲氧化鈉(11 mg)，在室溫進行一夜攪拌。於反應液加入水，將固體濾取後得到4-甲氧基-6-[(6-甲基吡啶-3-基)胺基]-2-(甲基磺醯基)嘧啶-5-甲醯胺(41 mg)。4-Chloro-6-[(6-methylpyridin-3-yl)amino]-2-(methylsulfonyl)pyrimidine-5-carboxamide (Production Example 303) (51 mg) and methanol (1 mL) of the mixture was added with sodium methoxide (11 mg) under ice cooling, and stirred overnight at room temperature. Water was added to the reaction mixture, and the solid was filtered to give 4-methoxy-6-[(6-methylpyridin-3-yl)amino]-2-(methylsulfonyl)pyrimidine-5- Indoleamine (41 mg).

製造例311Manufacturing Example 311

於4-{[3-(甲基胺基甲醯基)苯基]胺基}-2-(甲基磺醯基)-6-側氧基-1,6-二氫嘧啶-5-甲醯胺(製造例306)(500 mg)、二氯甲烷(40 mL)與甲醇(40mL)的混合物中，加入奧克森(註冊商標)(922 mg)與水(10 mL)的混合物，在室溫進行18小時攪拌。於反應液加入氯仿與水，將析出之固體經濾取並以水洗淨後得到4-{[3-(甲基胺基甲醯基)苯基]胺基}-2-(甲基亞磺醯基)-6-側氧基-1,6-二氫嘧啶-5-甲醯胺(234 mg)之淡黃色固體。4-{[3-(Methylaminomethylindenyl)phenyl]amino}-2-(methylsulfonyl)-6-oxooxy-1,6-dihydropyrimidine-5- A mixture of guanamine (manufacturing example 306) (500 mg), dichloromethane (40 mL) and methanol (40 mL) was added to a mixture of Oxon (registered trademark) (922 mg) and water (10 mL). Stir at room temperature for 18 hours. To the reaction mixture, chloroform and water were added, and the precipitated solid was filtered and washed with water to give 4-{[3-(methylaminomethylmethyl)phenyl]amino}-2-(methyl Sulfhydryl)-6-o-oxy-1,6-dihydropyrimidine-5-carboxamide (234 mg) as a pale yellow solid.

製造例339Manufacturing Example 339

於4-甲氧基-6-[(6-甲氧基吡啶-3-基)胺基]-2-(甲基磺醯基)嘧啶-5-甲醯胺(製造例337)(0.35 g)與水(2.2 mL)的混合物中加入濃鹽酸(2.2 mL)，在80℃進行1.5小時攪拌。將反應液冷卻後，加入1M氫氧化鈉水溶液幾乎成為中性後，將所生成的固體經濾取後得到4-[(6-甲氧基吡啶-3-基)胺基]-2-(甲基磺醯基)-6-側氧基-1,6-二氫嘧啶-5-甲醯胺(0.34 g)。4-methoxy-6-[(6-methoxypyridin-3-yl)amino]-2-(methylsulfonyl)pyrimidine-5-carboxamide (Production Example 337) (0.35 g Concentrated hydrochloric acid (2.2 mL) was added to a mixture with water (2.2 mL), and stirred at 80 ° C for 1.5 hours. After the reaction liquid was cooled, the 1 M sodium hydroxide aqueous solution was added to be almost neutral, and the resulting solid was filtered to give 4-[(6-methoxypyridin-3-yl)amino]-2-( Methylsulfonyl)-6-o-oxy-1,6-dihydropyrimidine-5-carboxamide (0.34 g).

製造例342Manufacturing example 342

於4,6-二氯-2-(甲基磺醯基)嘧啶-5-羧酸(1.50 g)與二氯甲烷(15 mL)的混合物中，冰冷下加入草醯氯(1.20 mL)及DMF(0.015 mL)，在冰冷中進行30分鐘攪拌，在室溫中進行2小時攪拌。減壓下將溶劑餾去後在甲苯共沸。將所得之殘渣溶解於THF後，在-10℃下滴入40%甲基胺水溶液。滴入終了後將反應液濃縮並加入水，將所成的固體經濾取並以水洗淨後得到白色固體。將該固體溶解於乙酸乙酯，以飽和食鹽水洗淨後，以無水硫酸鎂乾燥。將溶劑餾去，於所得之殘渣與二噁烷(20 mL)的混合物中，加入3-(甲基磺醯基)苯胺鹽酸鹽(432 mg)與N,N-二異丙基乙基胺(0.73 mL)，並在100℃下進行4小時攪拌。將反應液冷卻後以乙酸乙酯稀釋，以飽和食鹽水洗淨。以無水硫酸鎂乾燥後，將溶劑餾去，將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇=100：0-30：1)進行純化後得到4-氯-N-甲基-2-(甲基磺醯基)-6-{[3-(甲基磺醯基)苯基]胺基}嘧啶-5-甲醯胺(445 mg)之白色固體。To a mixture of 4,6-dichloro-2-(methylsulfonyl)pyrimidine-5-carboxylic acid (1.50 g) and dichloromethane (15 mL), EtOAc (1.20 mL) DMF (0.015 mL) was stirred for 30 minutes under ice cooling, and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and then azeotroped in toluene. After the obtained residue was dissolved in THF, a 40% aqueous methylamine solution was added dropwise at -10 °C. After the completion of the dropwise addition, the reaction mixture was concentrated and water was added, and the obtained solid was filtered and washed with water to give a white solid. The solid was dissolved in ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and a mixture of the obtained residue and dioxane (20 mL) was added to 3-(methylsulfonyl)aniline hydrochloride (432 mg) and N,N-diisopropylethyl Amine (0.73 mL) was stirred at 100 ° C for 4 hours. The reaction solution was cooled, diluted with ethyl acetate and washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform:methanol=100:0-30:1) to give 4-chloro-N-methyl- 2-(Methylsulfonyl)-6-{[3-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxamide (445 mg) as a white solid.

製造例346Manufacturing Example 346

於4-氯-2-(甲基磺醯基)-6-(喹啉-3-基胺基)嘧啶-5-甲醯胺(製造例344)(0.68 g)與乙酸鈉(0.80 g)的混合物中，加入DMF(7 mL)，在100℃進行6小時攪拌。將反應液恢復至室溫後，加入水，將所生成的固體經濾取後得到5-胺基甲醯基-2-(甲基磺醯基)-6-(喹啉-3-基胺基)嘧啶-4-基乙酸酯(0.71 g)。4-Chloro-2-(methylsulfonyl)-6-(quinolin-3-ylamino)pyrimidine-5-carboxamide (Production Example 344) (0.68 g) and sodium acetate (0.80 g) DMF (7 mL) was added to the mixture, and stirred at 100 ° C for 6 hours. After returning the reaction solution to room temperature, water was added, and the resulting solid was filtered to give 5-aminomethylmercapto-2-(methylsulfonyl)-6-(quinolin-3-ylamine) Pyrimidine-4-yl acetate (0.71 g).

製造例349Manufacturing example 349

於5-胺基甲醯基-2-(甲基磺醯基)-6-(喹啉-3-基胺基)嘧啶-4-基乙酸酯(製造例346)(0.71 g)中加入乙醇(14 mL)與THF(14 mL)，加入1M氫氧化鈉水溶液(6 mL)，在室溫進行1小時攪拌。加入1M鹽酸(6 mL)，將析出之固體經濾取並乾燥後得到2-(甲基磺醯基)-6-側氧基-4-(喹啉-3-基胺基)-1,6-二氫嘧啶-5-甲醯胺(0.63 g)。Addition to 5-aminomercapto-2-(methylsulfonyl)-6-(quinolin-3-ylamino)pyrimidin-4-yl acetate (Production Example 346) (0.71 g) Ethanol (14 mL) and THF (14 mL) were added 1M aqueous sodium hydroxide (6 mL) and stirred at room temperature for 1 hour. 1M Hydrochloric acid (6 mL) was added, and the precipitated solid was filtered and dried to give 2-(methylsulfonyl)-6-oxooxy-4-(quinolin-3-ylamino)-1. 6-Dihydropyrimidine-5-formamide (0.63 g).

製造例353Manufacturing Example 353

將3,5-二氯-6-乙基吡嗪-2-甲醯胺(600 mg)與3-(甲基磺醯基)苯胺(467mg)、N,N-二異丙基乙基胺(0.48 mL)與二噁烷(18 mL)的混合物，在封管中於170℃下進行17小時攪拌。冷卻後以乙酸乙酯與水進行分液操作，將有機層以飽和食鹽水洗淨後，以無水硫酸鎂乾燥。將溶劑餾去後，將殘渣以氯仿洗淨，將固體濾取並乾燥後得到5-氯-6-乙基-3-{[3-(甲基磺醯基)苯基]胺基}吡嗪-2-甲醯胺(412 mg)之黃色固體。3,5-Dichloro-6-ethylpyrazine-2-carboxamide (600 mg) with 3-(methylsulfonyl)aniline (467 mg), N,N-diisopropylethylamine A mixture of (0.48 mL) and dioxane (18 mL) was stirred at 170 ° C for 17 hours in a sealed tube. After cooling, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was washed with chloroform, and the solid was filtered and dried to give 5-chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyridinium A yellow solid of pyrazin-2-carbamide (412 mg).

製造例364Manufacturing Example 364

於4-氯-6-[(5-甲基吡啶-3-基)胺基]-2-(甲基磺醯基)嘧啶-5-甲醯胺(製造例359)(194 mg)與DMF(5 mL)的混合物中，加入乙酸鈉(257 mg)，在100℃進行5小時攪拌。將反應液冷卻後加入乙酸乙酯與水，將析出粉末經濾取、乾燥後得到淡黃色固體。於該固體與乙醇(5 mL)、甲醇(20 mL)、THF(5 mL)的混合物中，加入1M氫氧化鈉水溶液(3mL)，在室溫下進行1小時攪拌，在60℃進行1小時攪拌，在80℃進行1小時攪拌。將反應液冷卻後加入1M鹽酸(3 mL)，以氯仿-異丙醇萃取。於有機層加入矽膠，將溶劑餾去後，以矽膠管柱層析法(溶離液；氯仿：甲醇=100：0-20：1)進行純化後得到粗純化物。將此以少量甲醇洗淨後得到4-[(5-甲基吡啶-3-基)胺基]-2-(甲基磺醯基)-6-側氧基-1,6-二氫嘧啶-5-甲醯胺(27 mg)之黃色固體。4-Chloro-6-[(5-methylpyridin-3-yl)amino]-2-(methylsulfonyl)pyrimidine-5-carboxamide (Production Example 359) (194 mg) and DMF Sodium acetate (257 mg) was added to a mixture of (5 mL), and stirred at 100 ° C for 5 hours. After cooling the reaction mixture, ethyl acetate and water were added, and the precipitated powder was filtered and dried to give a pale yellow solid. A 1 M aqueous sodium hydroxide solution (3 mL) was added to a mixture of the solid and ethanol (5 mL), methanol (20 mL), THF (5 mL), and the mixture was stirred at room temperature for 1 hour and at 60 ° C for 1 hour. The mixture was stirred and stirred at 80 ° C for 1 hour. After the reaction mixture was cooled, 1M hydrochloric acid (3 mL) was evaporated and evaporated. The tantalum gum was added to the organic layer, and the solvent was distilled off, and then purified by silica gel column chromatography (solvent; chloroform:methanol = 100:0 to 20:1) to give a crude material. This was washed with a small amount of methanol to give 4-[(5-methylpyridin-3-yl)amino]-2-(methylsulfonyl)-6-o-oxy-1,6-dihydropyrimidine. -5-Methylamine (27 mg) as a yellow solid.

製造例397Manufacturing Example 397

於5-氯-6-乙基-3-{[4-(甲基磺醯基)苯基]胺基}吡嗪-2-甲醯胺(製造例394)(92 mg)與乙酸(2.5 mL)的混合物中，加入鎢酸鈉2水合物(29 mg)、30%過氧化氫水(0.15 mL)，在室溫進行30分鐘攪拌。於反應液加入水與乙酸乙酯後，加入1M氫氧化鈉水溶液，進行30分鐘攪拌後，進行分液操作。將有機層以無水硫酸鈉乾燥後過濾並濃縮。將所得之殘渣以乙酸乙酯洗淨後得到5-氯-6-乙基-3-{[4-(甲基磺醯基)苯基]胺基}吡嗪-2-甲醯胺(103 mg)。5-Chloro-6-ethyl-3-{[4-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Production Example 394) (92 mg) and acetic acid (2.5 To the mixture of mL), sodium tungstate 2 hydrate (29 mg) and 30% hydrogen peroxide water (0.15 mL) were added, and the mixture was stirred at room temperature for 30 minutes. After adding water and ethyl acetate to the reaction liquid, a 1 M aqueous sodium hydroxide solution was added thereto, and the mixture was stirred for 30 minutes, and then subjected to a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The obtained residue was washed with ethyl acetate to give 5-chloro-6-ethyl-3-{[4-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (103 Mg).

製造例398Manufacturing Example 398

於3,5-二氯-6-(1-羥基-1-甲基乙基)吡嗪-2-甲醯胺(2.64 g)與吡啶(30 mL)的混合物中，冰冷下加入甲磺醯氯化物(2.45 mL)。在室溫進行5小時攪拌後，減壓下餾去吡啶，將所得之殘渣以乙酸乙酯與水進行分液操作。將所得之有機層以10%檸檬酸水溶液、飽和碳酸氫鈉水溶液、飽和食鹽水洗淨並以無水硫酸鎂乾燥，將溶劑餾去後得到淡咖啡色糖漿狀物。於此加入乙醇(60 mL)與THF(30 mL)後，加入10%鈀載持碳(0.7 g)，於3氣壓氫氣環境下在室溫進行14小時攪拌。以矽藻石過濾後，將濾液減壓餾去，將殘渣以乙酸乙酯稀釋後，以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨。將溶劑餾去後，將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇=100：0-40：1)進行純化。將所得之粗純化物以二異丙醚洗淨後得到3,5-二氯-6-異丙基吡嗪-2-甲醯胺(632 mg)之白色固體。In a mixture of 3,5-dichloro-6-(1-hydroxy-1-methylethyl)pyrazine-2-carboxamide (2.64 g) and pyridine (30 mL), methanesulfonate was added under ice cooling. Chloride (2.45 mL). After stirring at room temperature for 5 hours, pyridine was distilled off under reduced pressure, and the obtained residue was partitioned between ethyl acetate and water. The obtained organic layer was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a pale brown syrup. After adding ethanol (60 mL) and THF (30 mL), 10% palladium-supported carbon (0.7 g) was added, and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere of 3 atmospheres. After filtering with diatomaceous earth, the filtrate was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and brine. After the solvent was distilled off, the residue was purified by silica gel column chromatography (solvent; chloroform:methanol=100:0-40:1). The obtained crude product was washed with diisopropyl ether to give 3,5-dichloro-6-isopropylpyrazine-2-carbamide ( 632 mg) as a white solid.

製造例399Manufacturing Example 399

於tert-丁基(1-甲基-4-側氧基環己基)胺甲酸酯(4.00 g)與甲醇(50 mL)的混合物中，加入甲酸銨(10.2 g)及水(5 mL)，進行1小時攪拌至完全溶解。加入10%鈀載持碳(2.0 g)，在室溫進行65小時攪拌。將不溶物以矽藻石過濾去除後，將溶劑餾去，於所得之殘渣中加入氯仿，以無水硫酸鎂乾燥。將溶劑餾去後得到tert-丁基(4-胺基-1-甲基環己基)胺甲酸酯(3.73 g)之無色糖漿狀物。Add ammonium formate (10.2 g) and water (5 mL) to a mixture of tert-butyl(1-methyl-4-oxocyclohexyl)carbamate (4.00 g) and methanol (50 mL) , stirring for 1 hour until completely dissolved. Carbon (2.0 g) was supported by the addition of 10% palladium and stirred at room temperature for 65 hours. After the insoluble material was removed by filtration with celite, the solvent was evaporated, and chloroform was added to the residue and dried over anhydrous magnesium sulfate. The solvent was distilled off to give tert-butyl(4-amino-1-methylcyclohexyl)carbamate (3.73 g) as a colorless syrup.

製造例400Manufacturing example 400

於tert-丁基(4-胺基-1-甲基環己基)胺甲酸酯(製造例399)(3.73 g)與乙醇(30 mL)的混合物中，冰冷下加入4M氯化氫乙酸乙酯溶液(30 mL)，在室溫下進行20小時攪拌。將析出固體經濾取並以乙酸乙酯洗淨後得到1-甲基環己烷-1,4-二胺2鹽酸鹽(2.10 g)之白色固體。In a mixture of tert-butyl(4-amino-1-methylcyclohexyl)carbamate (manufacturing example 399) (3.73 g) and ethanol (30 mL), 4M aqueous hydrogen chloride solution was added under ice cooling. (30 mL), stirring at room temperature for 20 hours. The precipitated solid was filtered and washed with ethyl acetate to give 1-methyl cyclohexane-1,4-diamine 2 hydrochloride (2.10 g).

製造例412Manufacturing Example 412

於tert-丁基4-(4,4,5,5-四甲基-1,3,2-二噁環戊硼烷-2-基)-3,6-二氫吡啶-1(2H)-羧酸酯(3.16 g)、4-溴-3-甲氧基-1-硝基苯(2.63 g)及DMF(31.6 mL)的混合物中，加入[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)、二氯甲烷加成物(0.50 g)與碳酸鉀(4.24 g)，在80℃進行4小時攪拌。將該混合物經減壓下濃縮後，加入水、乙酸乙酯，將不溶物以矽藻石過濾去除。將有機層以飽和食鹽水洗淨。以無水硫酸鎂乾燥後，將溶劑餾去，將殘渣於矽膠管柱層析法(溶離液；n-己烷：乙酸乙酯=1：0-2：1)進行純化後得到tert-丁基4-(2-甲氧基-4-硝基苯基)-3,6-二氫吡啶-1(2H)-羧酸酯(2.21 g)之黃色固體。Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)-3,6-dihydropyridine-1 (2H) -1,1'-bis(diphenyl) in a mixture of a carboxylate (3.16 g), 4-bromo-3-methoxy-1-nitrobenzene (2.63 g) and DMF (31.6 mL) Phosphyl)ferrocene]dichloropalladium(II), dichloromethane adduct (0.50 g) and potassium carbonate (4.24 g) were stirred at 80 ° C for 4 hours. After the mixture was concentrated under reduced pressure, water and ethyl acetate were added, and the insoluble material was removed by filtration. The organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 1:0 to 2:1) to afford tert-butyl. A yellow solid of 4-(2-methoxy-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.21 g).

製造例413Manufacturing Example 413

於tert-丁基4-(2-甲氧基-4-硝基苯基)-3,6-二氫吡啶-1(2H)-羧酸酯(製造例412)(2.21 g)、乙醇(40 mL)及THF(20 mL)的混合物中，加入10%鈀載持碳(1.0 g)，常壓氫氣環境下，在室溫進行3小時攪拌。以矽藻石過濾後，將濾液減壓餾去後得到tert-丁基4-(4-胺基-2-甲氧基苯基)哌啶-1-羧酸酯(1.97 g)之灰色固體。Tert-butyl 4-(2-methoxy-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (Production Example 412) (2.21 g), ethanol ( To a mixture of 40 mL) and THF (20 mL), 10% palladium-supported carbon (1.0 g) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere under normal pressure. After filtration through diatomaceous stone, the filtrate was evaporated under reduced pressure to give a pale solid of tert-butyl 4-(4-amino-2-methoxyphenyl)piperidine-1-carboxylate (1.97 g). .

製造例417Manufacturing Example 417

將5-氯-6-(1-羥基-1-甲基乙基)-3-{[4-(4-甲基吡嗪1-基)苯基]胺基}吡嗪-2-甲醯胺(製造例416)(430 mg)與乙酸(10 mL)的混合物，在120℃進行5小時攪拌。將反應液冷卻後，將溶劑餾去，加入水及飽和碳酸氫鈉水溶液使其中和。以乙酸乙酯萃取後，以飽和碳酸氫鈉水溶液、飽和食鹽水洗淨，以無水硫酸鎂乾燥。將溶劑餾去，將殘渣以二異丙醚洗淨後得到5-氯-6-異丙烯基-3-{[4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺(265 mg)之橙色固體。5-Chloro-6-(1-hydroxy-1-methylethyl)-3-{[4-(4-methylpyrazin-1-yl)phenyl]amino}pyrazine-2-carboxamidine A mixture of the amine (manufacturing Example 416) (430 mg) and acetic acid (10 mL) was stirred at 120 ° C for 5 hours. After cooling the reaction mixture, the solvent was distilled off, and water and a saturated aqueous sodium hydrogencarbonate solution were added to neutralize. After extracting with ethyl acetate, it was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was washed with diisopropyl ether to give 5-chloro-6-isopropenyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino} Pyrazine-2-carboxamide (265 mg) as an orange solid.

製造例430Manufacturing Example 430

於7-硝基-2H-1,4-苯並噁嗪-3(4H)-酮(2.0 g)、苯甲基三乙基銨氯化物(470 mg)、碳酸鉀(4.27 g)及乙腈(60 mL)的混合物中，加入1-溴-2-氯乙烷(1.28 mL)，在75℃進行3小時攪拌。將反應液冷卻後，加入飽和碳酸氫鈉水溶液後以乙酸乙酯萃取，將萃取液以飽和食鹽水洗淨。以無水硫酸鎂乾燥後，將溶劑減壓餾去，將殘渣於矽膠管柱層析法(溶離液；氯仿)進行純化後得到4-(2-氯乙基)-7-硝基-2H-1,4-苯並噁嗪-3(4H)-酮(1.92 g)之黃色粉末。7-Nitro-2H-1,4-benzoxazine-3(4H)-one (2.0 g), benzyltriethylammonium chloride (470 mg), potassium carbonate (4.27 g) and acetonitrile To the mixture (60 mL), 1-bromo-2-chloroethane (1.28 mL) was added and stirred at 75 ° C for 3 hours. After cooling the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified on silica gel column chromatography (solvent; chloroform) to give 4-(2-chloroethyl)-7-nitro-2H- Yellow powder of 1,4-benzoxazine-3(4H)-one (1.92 g).

製造例432Manufacturing Example 432

於4-(2-氯乙基)-7-硝基-2H-1,4-苯並噁嗪-3(4H)-酮(製造例430)(1.08 g)、碳酸鉀(0.87 g)及乙腈(10.8 mL)的混合物中加入1-甲基哌嗪(1.39 mL)，在80℃進行48小時攪拌。將反應液冷卻後，加入飽和碳酸氫鈉水溶液後以乙酸乙酯萃取，將萃取液以飽和食鹽水洗淨。以無水硫酸鎂乾燥後，將溶劑減壓餾去，將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇=100：0-20：1)進行純化後得到4-[2-(4-甲基哌嗪-1-基)乙基]-7-硝基-2H-1,4-苯並噁嗪-3(4H)-酮(690 mg)之黃色液體。4-(2-Chloroethyl)-7-nitro-2H-1,4-benzoxazine-3(4H)-one (Production Example 430) (1.08 g), potassium carbonate (0.87 g) and 1-Methylpiperazine (1.39 mL) was added to a mixture of acetonitrile (10.8 mL), and stirred at 80 ° C for 48 hours. After cooling the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel column (solvent; chloroform:methanol=100:0-20:1) to give 4-[2-(4) A yellow liquid of -methylpiperazin-1-yl)ethyl]-7-nitro-2H-1,4-benzoxazine-3(4H)-one (690 mg).

製造例440Manufacturing example 440

將3,5-二氯-6-(1-羥基-1-甲基乙基)吡嗪-2-甲醯胺(1.10 g)與4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]-3-(三氟甲基)苯胺(製造例436)(1.58g)、N,N-二異丙基乙基胺(0.80 mL)與二噁烷(31 mL)的混合物，在100℃進行135小時攪拌。冷卻後，加入水，以乙酸乙酯萃取。又，將不溶物過濾去除，將該不溶物溶解於甲醇後，與有機層混合。減壓下將溶劑餾去後乾燥，得到咖啡色固體。將該咖啡色固體與乙酸(30 mL)的混合物在120℃進行5小時攪拌。將溶劑餾去後，加入飽和碳酸氫鈉水溶液，將析出之固體經濾取並以水洗淨。將所得之固體以鹼性矽膠管柱層析法(溶離液；氯仿)進行純化後得到5-氯-6-異丙烯基-3-({4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]-3-(三氟甲基)苯基}胺基)吡嗪-2-甲醯胺(0.99 g)之黃色固體。3,5-Dichloro-6-(1-hydroxy-1-methylethyl)pyrazine-2-carboxamide (1.10 g) with 4-[4-(4-methylpiperazin-1- Piperidin-1-yl]-3-(trifluoromethyl)aniline (manufacturing example 436) (1.58 g), N,N-diisopropylethylamine (0.80 mL) and dioxane (31) The mixture of mL) was stirred at 100 ° C for 135 hours. After cooling, water was added and extracted with ethyl acetate. Further, the insoluble matter was removed by filtration, and the insoluble matter was dissolved in methanol, and then mixed with the organic layer. The solvent was distilled off under reduced pressure and dried to give a brown solid. The mixture of the brown solid and acetic acid (30 mL) was stirred at 120 ° C for 5 hours. After the solvent was distilled off, a saturated aqueous sodium hydrogencarbonate solution was added, and the precipitated solid was filtered and washed with water. The obtained solid was purified by basic gel column chromatography (solvent; chloroform) to give 5-chloro-6-isopropenyl-3-({4-[4-(4-methylpiperazine)- 1-Base)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide (0.99 g) as a yellow solid.

製造例444Manufacturing example 444

將乙酸鈀(188 mg)、1,1'-萘-2,2'-二基雙(二苯基膦)(781 mg)、碳酸銫(4.09 g)及THF(20 mL)的混合物進行30分鐘攪拌後，加入1-溴-3-甲氧基-5-硝基苯(1.94 g)、1-甲基哌嗪(2.76 mL)及THF(20 mL)的混合物，進行14小時加熱迴流。將反應液冷卻後，以乙酸乙酯稀釋並將不溶物過濾去除。將濾液以2M鹽酸進行萃取操作，將所得之水層以50%氫氧化鉀水溶液成為鹼性後，以氯仿萃取。將有機層以無水硫酸鎂乾燥後，將溶劑餾去，將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇=100：0-20：1)進行純化後得到1-(3-甲氧基-5-硝基苯基)-4-甲基哌嗪(1.01 g)之橙色糖漿狀物。A mixture of palladium acetate (188 mg), 1,1'-naphthalene-2,2'-diylbis(diphenylphosphine) (781 mg), cesium carbonate (4.09 g) and THF (20 mL) was carried out 30 After stirring for a minute, a mixture of 1-bromo-3-methoxy-5-nitrobenzene (1.94 g), 1-methylpiperazine (2.76 mL) and THF (20 mL) was then evaporated. After cooling the reaction mixture, it was diluted with ethyl acetate and the insoluble material was filtered. The filtrate was subjected to an extraction operation with 2M hydrochloric acid, and the obtained aqueous layer was made basic with 50% aqueous potassium hydroxide solution, and then extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform:methanol=100:0-20:1) to obtain 1-(3-A) An orange syrup of oxy-5-nitrophenyl)-4-methylpiperazine (1.01 g).

製造例454Manufacturing example 454

於tert-丁基4-(4-胺基-2-甲氧基苯基)哌啶-1-羧酸酯(製造例413)(4.25 g)與THF(100 mL)的混合物中，加入碳酸氫鈉(1.28 g)及水(30 mL)後，冰冷下滴入氯甲酸苯甲基(1.98 mL)，經一夜攪拌。加入水，以乙酸乙酯萃取後，以飽和食鹽水洗淨。以無水硫酸鎂乾燥後，將溶劑餾去，將殘渣於矽膠管柱層析法(溶離液；n-己烷：乙酸乙酯=2：1)進行純化後得到tert-丁基4-(4-{[(苯甲氧基)羰基]胺基}-2-甲氧基苯基)哌啶-1-羧酸酯(4.92 g)之無色非晶質。Adding carbonic acid to a mixture of tert-butyl 4-(4-amino-2-methoxyphenyl)piperidine-1-carboxylate (Production Example 413) (4.25 g) and THF (100 mL) After sodium hydrogenate (1.28 g) and water (30 mL), benzyl chloroformate (1.98 mL) was added dropwise under ice cooling, and stirred overnight. Water was added, and the mixture was extracted with ethyl acetate, and then washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 2:1) to afford tert-butyl 4-(4) -{[(Benzyloxy)carbonyl]amino}-2-methoxyphenyl)piperidine-1-carboxylate (4.92 g) as a colorless amorphous material.

製造例455Manufacturing Example 455

將tert-丁基4-(4-{[(苯甲氧基)羰基]胺基}-2-甲氧基苯基)哌啶-1-羧酸酯(製造例454)(4.92 g)、三氟乙酸(10 mL)及1,2-二氯乙烷(50 mL)的混合物在室溫進行1小時攪拌。將反應溶劑經減壓濃縮，於殘渣加入飽和碳酸氫鈉水溶液，以氯仿萃取。以無水硫酸鎂乾燥後，將溶劑餾去，於殘渣加入二乙醚並使其固體化後得到苯甲基(3-甲氧基-4-哌啶-4-基苯基)胺甲酸酯(3.24 g)之白色固體。Tert-butyl 4-(4-{[(benzyloxy)carbonyl]amino}-2-methoxyphenyl)piperidine-1-carboxylate (Production Example 454) (4.92 g), A mixture of trifluoroacetic acid (10 mL) and 1,2-dichloroethane (50 mL) was stirred at room temperature for 1 hour. The reaction solvent was concentrated under reduced pressure. After drying over anhydrous magnesium sulfate, the solvent was evaporated, and diethyl ether was added to the residue and solidified to give benzyl (3-methoxy-4-piperidin-4-ylphenyl)carbamate ( 3.24 g) of a white solid.

製造例464Manufacturing example 464

於苯甲基(3-甲氧基-4-哌啶-4-基苯基)胺甲酸酯(製造例455)(1.52 g)與1,2-二氯乙烷(70 mL)的混合物中，加入甲醛水(3.62 mL)及三乙酸基氫化硼鈉(1.42 g)，在室溫進行一夜攪拌。於反應液加入水及飽和碳酸氫鈉水溶液並以氯仿萃取，將有機層以無水硫酸鎂乾燥。將溶劑經減壓餾去後，將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇：飽和氨水=100：0：0-10：1：0.1)進行純化後得到苯甲基[3-甲氧基-4-(1-甲基哌啶-4-基)苯基]胺甲酸酯(1.26 g)之白色固體。a mixture of benzyl (3-methoxy-4-piperidin-4-ylphenyl)carbamate (manufacturing example 455) (1.52 g) and 1,2-dichloroethane (70 mL) Among them, formalin (3.62 mL) and sodium triacetate trihydride (1.42 g) were added, and stirred at room temperature overnight. Water and a saturated aqueous solution of sodium hydrogencarbonate were added to the mixture and the mixture was evaporated. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (solvent; chloroform:methanol: saturated aqueous ammonia=100:0:0-10:1:0.1) to afford benzyl [3] -Methoxy-4-(1-methylpiperidin-4-yl)phenyl]carbamate (1.26 g) as a white solid.

製造例467Manufacturing Example 467

氬氣環境下，於7-胺基-4-[3-(4-甲基哌嗪-1-基)丙基]-2H-1,4-苯並噁嗪-3(4H)-酮(製造例435)(300 mg)與THF(9 mL)的混合物中，將硼烷-四氫呋喃錯體(3.0 mL、1M THF溶液)在冰冷下慢慢滴入。滴入終了後在室溫下進行1小時攪拌，進一步在70℃進行3小時攪拌。於反應液，冰冷下慢慢加入甲醇(10 mL)後，繼續加入1M鹽酸(5 mL)以及1M氫氧化鈉水溶液(10 mL)，在室溫進行1小時攪拌。將反應液以水稀釋後，以乙酸乙酯萃取。將溶劑餾去後，將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇=100：0-20：1)進行純化後得到4-[3-(4-甲基哌嗪-1-基)丙基]-3,4-二氫-2H-1,4-苯並噁嗪-7-胺(120 mg)。7-Amino-4-[3-(4-methylpiperazin-1-yl)propyl]-2H-1,4-benzoxazine-3(4H)-one under argon ( In a mixture of the production example 435) (300 mg) and THF (9 mL), borane-tetrahydrofuran (3.0 mL, 1 M THF solution) was slowly added dropwise under ice cooling. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour, and further stirred at 70 ° C for 3 hours. After slowly adding methanol (10 mL) to the reaction mixture, the mixture was evaporated, and then, then, 1M hydrochloric acid (5 mL) and 1 M sodium hydroxide aqueous solution (10 mL) was added and stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (solvent; chloroform:methanol=100:0-20:1) to give 4-[3-(4-methylpiperazine-1- Propyl]-3,4-dihydro-2H-1,4-benzoxazine-7-amine (120 mg).

製造例468Manufacturing example 468

於苯甲基[3-甲氧基-4-(1-甲基哌啶-4-基)苯基]胺甲酸酯(製造例464)(1.26 g)、乙醇(20 mL)及THF(10 mL)的混合物中加入5%鈀載持碳(0.38 g)，常壓氫氣環境下，在室溫進行一夜攪拌。以矽藻石過濾後，將濾液減壓餾去後得到3-甲氧基-4-(1-甲基哌啶-4-基)苯胺(0.80 g)之淡粉紅色固體。Benzyl [3-methoxy-4-(1-methylpiperidin-4-yl)phenyl]carbamate (Production Example 464) (1.26 g), ethanol (20 mL), and THF ( To a mixture of 10 mL), 5% palladium-supported carbon (0.38 g) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After filtration over celite, the filtrate was evaporated under reduced pressure to give 3-methoxy-4-(1-methylpiperidin-4-yl)phenylamine (0.80 g) as a pale pink solid.

製造例472Manufacturing Example 472

於2-[甲基(3-硝基苯基)胺基]乙醇(780 mg)與二氯甲烷(20 mL)的混合物中，冰冷下依序加入三乙胺(0.66 mL)及甲磺醯氯化物(0.37 mL)，進行3小時攪拌。於反應液加入水，將有機層分離後以飽和食鹽水洗淨。以無水硫酸鎂乾燥後，將溶劑餾去後得到2-[甲基(3-硝基苯基)胺基]乙基甲磺酸酯(1.0 g)之黃色固體。In a mixture of 2-[methyl(3-nitrophenyl)amino]ethanol (780 mg) and dichloromethane (20 mL), triethylamine (0.66 mL) and methanesulfonate were added sequentially under ice cooling. Chloride (0.37 mL) was stirred for 3 hours. Water was added to the reaction mixture, and the organic layer was separated and washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated to give 2-[methyl(3-nitrophenyl)amino]ethyl methanesulfonate (1.0 g) as a yellow solid.

製造例473Manufacturing Example 473

將2-[甲基(3-硝基苯基)胺基]乙基甲磺酸酯(製造例472)(1.0 g)、1-甲基哌嗪(1.61 mL)及NMP(5 mL)的混合物使用微波反應裝置，在130℃進行30分鐘反應。將反應液以水稀釋後以氯仿與甲醇之混合溶劑(10：1)萃取後，以飽和食鹽水洗淨。以無水硫酸鎂乾燥後，將溶劑餾去，將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇：飽和氨水=10：1：0.1)進行純化後得到N-甲基-N-[2-(4-甲基哌嗪-1-基)乙基]-3-硝基苯胺(890 mg)之黃色油狀物。2-[Methyl(3-nitrophenyl)amino]ethyl methanesulfonate (Production Example 472) (1.0 g), 1-methylpiperazine (1.61 mL), and NMP (5 mL) The mixture was subjected to a reaction at 130 ° C for 30 minutes using a microwave reaction apparatus. The reaction solution was diluted with water, extracted with a mixed solvent of chloroform and methanol (10:1), and then washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform: methanol: saturated aqueous ammonia = 10:1:0.1) to give N-methyl-N-[ 2-(4-Methylpiperazin-1-yl)ethyl]-3-nitroaniline (890 mg) as a yellow oil.

製造例502Manufacturing Example 502

於8-(2-甲氧基-5-硝基苯基)-1，4-二噁-8-吖螺[4.5]癸烷(製造例495)(795 mg)與二噁烷(16 mL)的混合物中加入4M鹽酸(6.8 mL)，在80℃進行一夜攪拌。將反應液於減壓下濃縮，於濃縮液加入飽和碳酸氫鈉水溶液，以氯仿萃取後，以飽和食鹽水洗淨。以無水硫酸鈉乾燥後，將溶劑減壓下餾去，將殘渣於矽膠管柱層析法(溶離液；乙酸乙酯：n-己烷)進行純化後得到1-(2-甲氧基-5-硝基苯基)哌啶-4-酮(296 mg)。8-(2-Methoxy-5-nitrophenyl)-1,4-diox-8-indole [4.5] decane (manufacturing example 495) (795 mg) with dioxane (16 mL) 4M Hydrochloric acid (6.8 mL) was added to the mixture, and stirred at 80 ° C overnight. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by EtOAc EtOAc EtOAc. 5-Nitrophenyl)piperidin-4-one (296 mg).

製造例503Manufacturing Example 503

於1-(2-甲氧基-5-硝基苯基)哌啶-4-酮(製造例502)(296 mg)、1-甲基哌嗪(0.20 mL)及1,2-二氯乙烷(11 mL)的混合物中，加入三乙酸基氫化硼鈉(385 mg)後在室溫進行一夜攪拌。於反應液中加入水及飽和碳酸氫鈉水溶液並以氯仿萃取，將有機層以無水硫酸鈉乾燥。將溶劑減壓餾去，將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇=100：0-10：1)進行純化後得到1-[1-(2-甲氧基-5-硝基苯基)哌啶-4-基]-4-甲基哌嗪(0.40 g)之褐色油狀物。1-(2-Methoxy-5-nitrophenyl)piperidin-4-one (Production Example 502) (296 mg), 1-methylpiperazine (0.20 mL), and 1,2-dichloro A mixture of ethane (11 mL) was added with sodium triacetate hydride (385 mg) and stirred at room temperature overnight. Water and a saturated aqueous solution of sodium hydrogencarbonate were added and the mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; chloroform:methanol=100:0-10:1) to give 1-[1-(2-methoxy-5- Nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0.40 g) as a brown oil.

製造例516Manufacturing Example 516

於1-氟-2-甲基-4-硝基苯(3.0 g)、碳酸鉀(5.35 g)及DMF(30 mL)的混合物中，加入1,4-二噁-8-吖螺[4.5]癸烷(4.15 g)，在80℃進行20小時攪拌。將反應液冷卻後，以乙酸乙酯稀釋，以水及飽和食鹽水洗淨。以無水硫酸鎂乾燥後，將溶劑餾去，將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇=100：0-100：1)進行純化後得到8-(2-甲基-4-硝基苯基)-1,4-二噁-8-吖螺[4.5]癸烷(5.13 g)之黃色固體。In a mixture of 1-fluoro-2-methyl-4-nitrobenzene (3.0 g), potassium carbonate (5.35 g) and DMF (30 mL), 1,4-dioxa-8-xanthene [4.5 ] decane (4.15 g), stirred at 80 ° C for 20 hours. The reaction solution was cooled, diluted with ethyl acetate, and washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform:methanol=100:0-100:1) to give 8-(2-methyl-4). -Nitrophenyl)-1,4-dioxa-8-indole [4.5] decane (5.13 g) as a yellow solid.

製造例545Manufacturing Example 545

於5-氯-6-(2-羥基丙烷-2-基)-3-{[3-甲氧基-4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺(製造例544)(300 mg)與三氟乙酸(3 mL)的混合液中，冰冷下加入三乙基矽烷(0.55 mL)，冰冷下進行10分鐘攪拌，進一步在室溫進行22小時攪拌。將反應液濃縮後，將殘渣以氯仿稀釋，以飽和碳酸氫鈉水溶液洗淨。以無水硫酸鎂乾燥後，將溶劑餾去，將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇：飽和氨水=100：0：0-20：1：0.1)進行純化後得到粗生成物。將所得之粗生成物以二異丙醚洗淨後得到5-氯-6-異丙基-3-{[3-甲氧基-4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺(219 mg)之橙色固體。5-Chloro-6-(2-hydroxypropan-2-yl)-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine 2-Carboxyamine (manufacturing example 544) (300 mg) and trifluoroacetic acid (3 mL) were added to triethyl decane (0.55 mL) under ice cooling, and stirred for 10 minutes under ice cooling, further in the room. The mixture was stirred for 22 hours at a temperature. After concentrating the reaction mixture, the residue was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform: methanol: saturated aqueous ammonia = 100:0:0-20:1:0.1). Things. The obtained crude product was washed with diisopropyl ether to give 5-chloro-6-isopropyl-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)benzene. An orange solid of pyridyl-2-carboxamide (219 mg).

以上述製造例所製造之製造例化合物、及與上述製造例的相同方法下，使用各對應原料所製造之製造例化合物的化學結構如表7～表47所示。又，這些製造例化合物之製造方法及物理化學的數據如表48～表84所示。The chemical composition of the production example compound produced by using the corresponding raw materials in the production example compound produced in the above production example and the same method as in the above production example is shown in Tables 7 to 47. Further, the methods for producing the compounds of the examples and the physicochemical data are shown in Tables 48 to 84.

實施例4Example 4

將4-{[2-(異丙基磺醯基)苯基]胺基}-2-(甲基磺醯基)-6-側氧基-1,6-二氫嘧啶-5-甲醯胺(製造例294)(200 mg)、1-(胺基甲基)-N,N-二甲基環己基胺(409 mg)與NMP(1 mL)的混合物，使用微波反應裝置在180℃進行10分鐘加熱。將反應液冷卻後，以乙酸乙酯稀釋，將析出之結晶以濾取、乙酸乙酯洗淨後得到白色固體。於此加入乙醇與水之混合溶劑並加熱後冷卻，將析出之固體濾取後得到2-({[1-(二甲胺)環己基]甲基}胺基)-4-{[2-(異丙基磺醯基)苯基]胺基}-6-側氧基-1,6-二氫嘧啶-5-甲醯胺(136 mg)之白色固體。4-{[2-(Isopropylsulfonyl)phenyl]amino}-2-(methylsulfonyl)-6-oxooxy-1,6-dihydropyrimidine-5-formamidine Mixture of amine (manufacturing example 294) (200 mg), 1-(aminomethyl)-N,N-dimethylcyclohexylamine (409 mg) and NMP (1 mL) using a microwave reaction apparatus at 180 ° C Heat for 10 minutes. The reaction liquid was cooled, and the mixture was diluted with ethyl acetate. Here, a mixed solvent of ethanol and water is added, and after heating, it is cooled, and the precipitated solid is filtered to obtain 2-({[1-(dimethylamine)cyclohexyl]methyl}amino)-4-{[2- (Isopropylsulfonyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide (136 mg) as a white solid.

實施例19Example 19

將4-{[2-(異丙基磺醯基)苯基]胺基}-2-(甲基磺醯基)-6-側氧基-1,6-二氫嘧啶-5-甲醯胺(製造例294)(200 mg)、tert-丁基 2-(胺基甲基)哌啶-1-羧酸酯(1.12 g)與NMP(1 mL)的混合物，使用微波反應裝置，在180℃進行10分鐘加熱。冷卻反應液後，以乙酸乙酯稀釋，以水、飽和食鹽水洗淨。以無水硫酸鎂乾燥後，將溶劑餾去，將殘渣於矽膠管柱層析法(氯仿：甲醇=100：0～20：1)進行純化後得到白色非晶質。於該白色非晶質、乙酸乙酯(10 mL)與乙醇(5 mL)的混合物中，冰冷下加入4M氯化氫乙酸乙酯溶液(5 mL)，在室溫下進行4小時攪拌。將析出之固體經濾取、乾燥後得到4-{[2-(異丙基磺醯基)苯基]胺基}-6-側氧基-2-[(哌啶-2-基甲基)胺基]-1,6-二氫嘧啶-5-甲醯胺　鹽酸鹽(126 mg)之白色固體。4-{[2-(Isopropylsulfonyl)phenyl]amino}-2-(methylsulfonyl)-6-oxooxy-1,6-dihydropyrimidine-5-formamidine A mixture of the amine (manufacturing example 294) (200 mg), tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (1.12 g) and NMP (1 mL) using a microwave reaction apparatus Heating was carried out at 180 ° C for 10 minutes. The reaction solution was cooled, diluted with ethyl acetate, and washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 20:1) to give white amorphous material. To a mixture of the white amorphous material, ethyl acetate (10 mL) and ethanol (5 mL), 4M hydrogen chloride ethyl acetate solution (5 mL) was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. The precipitated solid is filtered and dried to give 4-{[2-(isopropylsulfonyl)phenyl]amino}-6-o-oxo-2-[(piperidin-2-ylmethyl) Amino]-1,6-dihydropyrimidine-5-carboxamide hydrochloride (126 mg) as a white solid.

實施例29Example 29

於tert-丁基3-[(5-胺基甲醯基-4-{[2-(異丙基磺醯基)苯基]胺基}-6-側氧基-1,6-二氫嘧啶-2-基)胺基]哌啶-1-羧酸酯(實施例28)(299 mg)與乙酸乙酯(3 mL)的混合物中，冰冷下加入4M氯化氫乙酸乙酯溶液(2.7 mL)，在室溫下進行1小時攪拌。將析出之固體經濾取、乾燥後得到4-{[2-(異丙基磺醯基)苯基]胺基}-6-側氧基-2-(哌啶-3-基胺基)-1,6-二氫嘧啶-5-甲醯胺2鹽酸鹽(194 mg)之白色固體。Tert-butyl 3-[(5-aminomethylmercapto-4-{[2-(isopropylsulfonyl)phenyl]amino}-6-o-oxy-1,6-dihydrol Pyrimidine-2-yl)amino]piperidine-1-carboxylate (Example 28) (299 mg) in EtOAc (3 mL) EtOAc ), stirring was carried out for 1 hour at room temperature. The precipitated solid is filtered and dried to give 4-{[2-(isopropylsulfonyl)phenyl]amino}-6-o-oxo-2-(piperidin-3-ylamino) -1,6-Dihydropyrimidine-5-carboxamide 2 hydrochloride (194 mg) as a white solid.

實施例31Example 31

於4-{[2-(異丙基磺醯基)苯基]胺基}-6-側氧基-2-(哌啶-3-基胺基)-1,6-二氫嘧啶-5-甲醯胺2鹽酸鹽(實施例29)(67 mg)與吡啶(1.3 mL)的混合物中，冰冷下加入甲磺醯氯化物(0.10 mL)，進行1小時攪拌。於反應系加入乙醇後，濃縮反應系，將所得之殘渣以氯仿、飽和碳酸氫鈉水溶液進行分液操作，乾燥有機層。將有機層濃縮並以甲苯共沸後，將所得之殘渣以乙酸乙酯-己烷固體化。將所得之固體以乙醇進行再結晶後得到4-{[2-(異丙基磺醯基)苯基]胺基}-2-{[1-(甲基磺醯基)哌啶-3-基]胺基}-6-側氧基-1,6-二氫嘧啶-5-甲醯胺(43 mg)。4-{[2-(Isopropylsulfonyl)phenyl]amino}-6-oxo-2-(piperidin-3-ylamino)-1,6-dihydropyrimidine-5 To a mixture of tolamine 2 hydrochloride (Example 29) (67 mg) and pyridine (1.3 mL), methanesulfonium chloride (0.10 mL) was added under ice cooling, and stirred for 1 hour. After adding ethanol to the reaction system, the reaction system was concentrated, and the obtained residue was subjected to liquid separation operation using chloroform and a saturated aqueous sodium hydrogencarbonate solution, and the organic layer was dried. After the organic layer was concentrated and azeotroped with toluene, the obtained residue was solidified ethyl acetate-hexane. The obtained solid was recrystallized from ethanol to give 4-{[2-(isopropylsulfonyl)phenyl]amino}-2-{[1-(methylsulfonyl)piperidin-3- Amino]-6-o-oxy-1,6-dihydropyrimidine-5-carboxamide (43 mg).

實施例37Example 37

將4-{[3-(甲基胺基甲醯基)苯基]胺基}-2-(甲基亞磺醯基)-6-側氧基-1,6-二氫嘧啶-5-甲醯胺(製造例311)(234 mg)、1-(胺基甲基)環己烷胺(172 mg)與NMP(2 mL)的混合物，在80℃進行30分鐘攪拌。將反應液冷卻後，以乙酸乙酯稀釋，將析出之固體經濾取。將此在乙醇-水中加熱、洗淨後得到2-{[(1-胺基環己基)甲基]胺基}-4-{[3-(甲基胺基甲醯基)苯基]胺基}-6-側氧基-1,6-二氫嘧啶-5-甲醯胺(215 mg)之白色固體。4-{[3-(Methylaminomethylindenyl)phenyl]amino}-2-(methylsulfinyl)-6-o-oxy-1,6-dihydropyrimidine-5- A mixture of formamide (Production Example 311) (234 mg), 1-(aminomethyl)cyclohexaneamine (172 mg) and NMP (2 mL) was stirred at 80 ° C for 30 minutes. After cooling the reaction mixture, it was diluted with ethyl acetate, and the precipitated solid was filtered. This was heated in ethanol-water and washed to give 2-{[(1-aminocyclohexyl)methyl]amino}-4-{[3-(methylaminomethylindenyl)phenyl]amine. A white solid of -6-o-oxy-1,6-dihydropyrimidine-5-carboxamide (215 mg).

實施例84Example 84

將5-氯-6-乙基-3-{[3-(甲基磺醯基)苯基]胺基}吡嗪-2-甲醯胺(製造例353)(150 mg)、1-(胺基甲基)環己烷胺(163 mg)與NMP(1 mL)的混合物，使用微波反應裝置在180℃進行20分鐘加熱。冷卻反應液，加入乙酸乙酯與水並進行30分鐘攪拌後，將析出粉末經濾取。將此以乙醇-水(1：1)加熱、洗淨後得到5-{[(1-胺基環己基)甲基]胺基}-6-乙基-3-{[3-(甲基磺醯基)苯基]胺基}吡嗪-2-甲醯胺(112 mg)之白色固體。5-Chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Production Example 353) (150 mg), 1-( A mixture of aminomethyl)cyclohexaneamine (163 mg) and NMP (1 mL) was heated at 180 ° C for 20 minutes using a microwave reaction apparatus. The reaction solution was cooled, and ethyl acetate and water were added thereto, and the mixture was stirred for 30 minutes, and then the precipitated powder was filtered. This was heated with ethanol-water (1:1) and washed to give 5-{[(1-aminocyclohexyl)methyl]amino}-6-ethyl-3-{[3-(methyl Sulfhydryl)phenyl]amino}pyrazine-2-carboxamide (112 mg) as a white solid.

實施例146Example 146

將3,5-二氯-6-乙基吡嗪-2-甲醯胺(200 mg)、3-氯-4-甲基磺醯基苯胺(374 mg)與NMP(1 mL)的混合物，使用微波反應裝置在230℃進行1小時攪拌。繼續於該反應液中加入反式-4-胺基環己醇(524 mg)，使用微波反應裝置，在190℃進行30分鐘攪拌。冷卻反應液後，以乙酸乙酯與水進行分液操作，將有機層以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨。以無水硫酸鎂乾燥後，將溶劑餾去，將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇=10：0-30：1)進行純化後得到粗純化物。將此以乙醇加熱、洗淨後得到淡黃色固體。於此加入乙酸乙酯並加熱，過濾去除不溶物後濃縮濾液。將濾液濃縮後以乙醇進行加熱洗淨後得到3-{[3-氯-4-(甲基磺醯基)苯基]胺基}-6-乙基-5-[(反式-4-羥基環己基)胺基]吡嗪-2-甲醯胺(39 mg)之淡黃色固體。a mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (200 mg), 3-chloro-4-methylsulfonylaniline (374 mg) and NMP (1 mL), Stirring was carried out at 230 ° C for 1 hour using a microwave reaction apparatus. Further, trans-4-aminocyclohexanol (524 mg) was added to the reaction mixture, and the mixture was stirred at 190 ° C for 30 minutes using a microwave reactor. After cooling the reaction mixture, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform:methanol = 10:0-30:1) to give a crude material. This was heated with ethanol and washed to give a pale yellow solid. Ethyl acetate was added thereto and heated, and the insoluble material was filtered to remove the filtrate. The filtrate was concentrated and washed with ethanol to give 3-{[3-chloro-4-(methylsulfonyl)phenyl]amino}-6-ethyl-5-[(trans-4- Hydroxycyclohexyl)amino]pyrazine-2-carboxamide (39 mg) as a pale yellow solid.

實施例159Example 159

於5-[(反式-4-羥基環己基)胺基]-3-{[3-(甲基磺醯基)苯基〕胺基}吡嗪-2-甲醯胺(實施例111)(298mg)、氯仿(40mL)與乙腈(10mL)的混合物中加入N-氯琥珀酸亞胺(108mg)，在70℃進行8小時攪拌。將反應液冷卻後，加入矽膠將溶劑餾去後，藉由矽膠管柱層析法(溶離液；氯仿：甲醇=10：0-10：1)進行純化。將所得之粗純化物藉由氯仿固體化並經濾取。將所得之固體以乙酸乙酯進行加熱、洗淨後得到6-氯-5-〔(反式-4-羥基環己基)胺基〕-3-{〔3-(甲基磺醯基)苯基〕胺基}吡嗪-2-甲醯胺(189mg)之白色固體。5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 111) N-chlorosuccinimide (108 mg) was added to a mixture of (298 mg), chloroform (40 mL) and acetonitrile (10 mL), and stirred at 70 ° C for 8 hours. After the reaction liquid was cooled, the solvent was distilled off by adding a silicone resin, and then purified by a silica gel column chromatography (elut solution; chloroform:methanol = 10:0 to 10:1). The resulting crude purified material was solidified by chloroform and filtered. The obtained solid was heated with ethyl acetate and washed to give 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)benzene. A white solid of pyridyl-2-carboxamide (189 mg).

實施例181Example 181

於5-〔(反式-4-羥基環己基)胺基〕-3-{〔3-(甲基磺醯基)苯基〕胺基}吡嗪-2-甲醯胺(實施例111)(150mg)、氯仿(40mL)與乙腈(20mL)的混合物中加入N-溴琥珀酸亞胺(69mg)，在室溫下進行2小時攪拌。於反應液加入矽膠，將溶劑餾去後以矽膠管柱層析法(溶離液；氯仿：甲醇=10：0-10：1)進行純化。將所得之粗純化物以乙酸乙酯進行固體化、洗淨後得到6-溴-5-〔(反式-4-羥基環己基)胺基〕-3-{〔3-(甲基磺醯基)苯基〕胺基}吡嗪-2-甲醯胺(130mg)之淡黃色固體。5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 111) N-bromosuccinimide (69 mg) was added to a mixture of (150 mg), chloroform (40 mL) and acetonitrile (20 mL), and the mixture was stirred at room temperature for 2 hours. The tantalum gum was added to the reaction liquid, and the solvent was distilled off, followed by purification by a gel column chromatography (elut solution; chloroform:methanol = 10:0 to 10:1). The obtained crude purified product was solidified with ethyl acetate and washed to give 6-bromo-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonium) Phenyl]amino]amino}pyrazine-2-carboxamide (130 mg) as a pale yellow solid.

實施例190Example 190

於5-[(反式-4-羥基環己基)胺基]-3-{[3-(甲基磺醯基)苯基]胺基}吡嗪-2-甲醯胺(實施例111)(150 mg)、氯仿(40 mL)與乙腈(20 mL)的混合物中，加入N-碘琥珀酸亞胺(87 mg)，在室溫下進行2小時攪拌。於反應液加入矽膠，餾去溶劑後以矽膠管柱層析法(溶離液；氯仿：甲醇=10：0-10：1)進行純化。將所得之粗純化物以乙酸乙酯固體化、洗淨後得到5-[(反式-4-羥基環己基)胺基]-6-碘-3-{[3-(甲基磺醯基)苯基]胺基}吡嗪-2-甲醯胺(153 mg)之淡黃色固體。5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 111) N-iodosuccinimide (87 mg) was added to a mixture of (150 mg), chloroform (40 mL) and acetonitrile (20 mL), and stirred at room temperature for 2 hours. The tantalum gum was added to the reaction mixture, and the solvent was distilled off, followed by purification by a silica gel column chromatography (solvent; chloroform:methanol = 10:0 to 10:1). The obtained crude purified product was solidified with ethyl acetate and washed to give 5-[(trans-4-hydroxycyclohexyl)amino]-6-iodo-3-{[3-(methylsulfonyl) Phenyl]amino}pyrazine-2-carboxamide (153 mg) as a pale yellow solid.

實施例196Example 196

將5-氯-6-乙基-3-{[3-(甲基磺醯基)苯基]胺基}吡嗪-2-甲醯胺(製造例353)(8.8 mg)、1-甲基-哌啶-3-基胺(8.0 mg)與NMP(0.5 mL)的混合物，使用微波反應裝置，在190℃進行30分鐘加熱。將反應液冷卻後，將有機層減壓餾去，將殘渣以HPLC(管柱：Sun Fire(註冊商標)C18、5μm、19mmx100mm、溶劑：MeOH/0.1% HCOOH-H2 O=10/90(0 min)-10/90(1 min)-95/5(9 min)-95/5(12 min)、流速：25mL/min)進行分取純化後得到(6-乙基-5-[(1-甲基哌啶-3-基)胺基]-3-{[3-(甲基磺醯基)苯基]胺基}吡嗪-2-甲醯胺(2.4 mg)。5-Chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Production Example 353) (8.8 mg), 1-A A mixture of benzyl-piperidin-3-ylamine (8.0 mg) and NMP (0.5 mL) was heated at 190 ° C for 30 minutes using a microwave reaction apparatus. After the reaction liquid was cooled, the organic layer was evaporated under reduced pressure, and the residue was applied to HPLC (column: Sun Fire (registered trademark) C18, 5 μm, 19 mm x 100 mm, solvent: MeOH/0.1% HCOOH-H 2 O = 10/90 ( 0 min) -10/90 (1 min) - 95/5 (9 min) - 95/5 (12 min), flow rate: 25 mL / min), after fractionation and purification, (6-ethyl-5-[( 1-Methylpiperidin-3-yl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (2.4 mg).

實施例302Example 302

於5-[(4-胺基-4-甲基環己基)胺基]-3-{[3-(甲基磺醯基)苯基]胺基}-6-丙基吡嗪-2-甲醯胺(實施例301)(89 mg)與二氯甲烷(5 mL)的混合物中，加入甲醛水(0.30 mL)及三乙酸基氫化硼鈉(82 mg)，在室溫下進行1.5小時攪拌。將反應液以氯仿稀釋後，以飽和碳酸氫鈉水溶液洗淨，以無水硫酸鎂乾燥。過濾去除乾燥劑後加入矽膠，將溶劑餾去，將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇：飽和氨水=10：0：0-10：1：0.1)進行純化。將所得之殘渣以乙酸乙酯洗淨後得到5-{[4-(二甲胺)-4-甲基環己基]胺基}-3-{[3-(甲基磺醯基)苯基]胺基}-6-丙基吡嗪-2-甲醯胺(31 mg)之淡黃色固體。5-[(4-Amino-4-methylcyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}-6-propylpyrazine-2- To a mixture of formamide (Example 301) (89 mg) and dichloromethane (5 mL), add formaldehyde water (0.30 mL) and sodium triacetate sodium hydride (82 mg) at room temperature for 1.5 hours. Stir. The reaction mixture was diluted with chloroform, washed with saturated aqueous sodium hydrogen sulfate and dried over anhydrous magnesium sulfate. After the desiccant was removed by filtration, the oxime gum was added, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; chloroform: methanol: saturated aqueous ammonia = 10:0:0-10:1:0.1). The obtained residue was washed with ethyl acetate to give 5-{[4-(dimethylamine)-4-methylcyclohexyl]amino}-3-{[3-(methylsulfonyl)phenyl. Amino}-6-propylpyrazine-2-carboxamide (31 mg) as a pale yellow solid.

實施例309Example 309

於6-乙基-5-[(順式-4-羥基-4-甲基環己基)胺基]-3-[(4-甲基-3-硝基苯基)胺基]吡嗪-2-甲醯胺(實施例308)(242 mg)與甲醇(10 mL)的混合物中，加入5%鈀載持碳(25 mg)，氫氣環境下，在室溫下進行4小時攪拌。將反應液過濾後，將濾液減壓濃縮後得到3-[(3-胺基-4-甲基苯基)胺基]-6-乙基-5-[(順式-4-羥基-4-甲基環己基)胺基]吡嗪-2-甲醯胺(162 mg)之綠色固體。To 6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-[(4-methyl-3-nitrophenyl)amino]pyrazine- To a mixture of 2-carbamide (Example 308) (242 mg) and methanol (10 mL), 5% palladium-supported carbon (25 mg) was added, and the mixture was stirred at room temperature for 4 hours under hydrogen atmosphere. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure to give 3-[(3-amino-4-methylphenyl)amino]-6-ethyl-5-[(cis-4-hydroxy-4) -Methylcyclohexyl)amino]pyrazine-2-carboxamide (162 mg) as a green solid.

實施例310Example 310

於3-[(3-胺基-4-甲基苯基)胺基]-6-乙基-5-[(順式-4-羥基-4-甲基環己基)胺基]吡嗪-2-甲醯胺(實施例309)(150 mg)、THF(2 mL)及DMF(2 mL)的混合物中，冰冷下加入N,N-二異丙基乙基胺(49 mg)及丙烯酸氯化物(34 mg)，進行30分鐘攪拌。將反應液注入於水中，以乙酸乙酯萃取。將有機層以水、飽和食鹽水之順次洗淨後，以無水硫酸鈉乾燥，將溶劑經減壓餾去。將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇)進行純化後得到3-{[3-(丙烯醯基胺基)-4-甲基苯基]胺基}-6-乙基-5-[(順式-4-羥基-4-甲基環己基)胺基]吡嗪-2-甲醯胺(48 mg)之淡黃色粉末。3-[(3-Amino-4-methylphenyl)amino]-6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]pyrazine- To a mixture of 2-carbamide (Example 309) (150 mg), THF (2 mL) and DMF (2 mL), N,N-diisopropylethylamine (49 mg) Chloride (34 mg) was stirred for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (solvent; chloroform:methanol) to give 3-{[3-(propenylamino)-4-methylphenyl]amino}-6-ethyl -5-[(cis-4-Hydroxy-4-methylcyclohexyl)amino]pyrazine-2-carboxamide (48 mg) as a pale yellow powder.

實施例343Example 343

於5-[(反式-4-羥基環己基)胺基]-6-異丙烯基-3-{[4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺(實施例342)(205 mg)、乙醇(20 mL)與THF(10 mL)的混合物中，氫氣環境下加入10%鈀載持碳(100 mg)，在室溫下進行18小時攪拌。將觸媒過濾去除後，將溶劑餾去，將殘渣以鹼性矽膠管柱層析法(溶離液；氯仿)進行純化。將所得之黃色固體以乙酸乙酯洗淨後得到5-[(反式-4-羥基環己基)胺基]-6-異丙基-3-{[4-(4-甲基哌嗪-1-基)苯基]胺基}吡嗪-2-甲醯胺(136 mg)之黃色固體。5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropenyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine a mixture of 2-carboxime (Example 342) (205 mg), ethanol (20 mL) and THF (10 mL), 10% palladium-supported carbon (100 mg) in a hydrogen atmosphere at room temperature Stir for 18 hours. After the catalyst was removed by filtration, the solvent was distilled off, and the residue was purified by basic gel column chromatography (solvent; chloroform). The obtained yellow solid was washed with ethyl acetate to give 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazine)- 1-Phenyl)phenyl]amino}pyrazine-2-carboxamide (136 mg) as a yellow solid.

實施例381Example 381

於tert-丁基4-[4-({3-胺基甲醯基-5-乙基-6-[(反式-4-羥基環己基)胺基]吡嗪-2-基}胺基)-2-甲氧基苯基]哌啶-1-羧酸酯(實施例382)(270 mg)與乙酸乙酯(10 mL)的混合物中，冰冷下加入4M氯化氫乙酸乙酯溶液(4 mL)後，在室溫下進行1小時攪拌。將反應液減壓濃縮，於殘渣加入飽和碳酸氫鈉水溶液、氯仿，將析出之固體經濾取、乾燥後得到6-乙基-5-[(反式-4-羥基環己基)胺基]-3-[(3-甲氧基-4-哌啶-4-基苯基)胺基]吡嗪-2-甲醯胺(85 mg)之淡黃色固體。Tert-butyl 4-[4-({3-aminocarbamimido-5-ethyl-6-[(trans-4-hydroxycyclohexyl)amino]pyrazin-2-yl}amino) a mixture of 2-methoxyphenyl]piperidine-1-carboxylate (Example 382) (270 mg) and ethyl acetate (10 mL). After mL), stirring was carried out for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc m.) 3-[(3-Methoxy-4-piperidin-4-ylphenyl)amino]pyrazine-2-carboxamide (85 mg) as a pale yellow solid.

實施例405Example 405

於6-乙基-5-[(反式-4-羥基環己基)胺基]-3-[(4-哌啶-4-基苯基)胺基]吡嗪-2-甲醯胺(實施例358)(43 mg)與二氯乙烷(1 mL)的混合物中，冰冷下加入吡啶(0.01 mL)及乙酸酐(0.01 mL)，在室溫下進行20分鐘攪拌。於反應液加入飽和碳酸氫鈉水溶液後，使用氯仿與飽和碳酸氫鈉水溶液進行分液操作。將有機層使用無水硫酸鈉乾燥後濃縮，將所得之殘渣以乙酸乙酯-己烷固體化後得到3-{[4-(1-乙醯基哌啶-4-基)苯基]胺基}-6-乙基-5-[(反式-4-羥基環己基)胺基]吡嗪-2-甲醯胺(26 mg)之白色固體。To 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-[(4-piperidin-4-ylphenyl)amino]pyrazine-2-carboxamide ( Example 358) A mixture of (43 mg) and dichloroethane (1 mL) was added pyridine (0.01 mL) and acetic anhydride (0.01 mL) under ice cooling, and stirred at room temperature for 20 min. After adding a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture, a liquid separation operation was carried out using chloroform and a saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated, and then evaporated to ethyl acetate-hexane to give 3-{[4-(1-ethylhydrazinopiperidin-4-yl)phenyl]amine }-6-Ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide (26 mg) as a white solid.

實施例436Example 436

於甲基4-[(5-胺基甲醯基-3-乙基-6-{[4-(4-甲基哌嗪-1-基)-3-(三氟甲基)苯基]胺基}吡嗪-2-基)胺基]環己烷羧酸酯(實施例435)(126 mg)、THF(2 mL)及甲醇(2 mL)的混合物中，加入10%氫氧化鈉水溶液(1 mL)，進行2小時加熱迴流。於反應液加入10%鹽酸，將pH成為約7，將所生成的固體進行濾取。將該固體以矽膠管柱層析法(溶離液；氯仿：甲醇)進行純化後得到低極性生成物之4-[(5-胺基甲醯基-3-乙基-6-{[4-(4-甲基哌嗪-1-基)-3-(三氟甲基)苯基]胺基}吡嗪-2-基)胺基]環己烷羧酸(實施例436)(47 mg)的淡黃白色粉末、及高極性生成物之4-[(5-胺基甲醯基-3-乙基-6-{[4-(4-甲基哌嗪-1-基)-3-(三氟甲基)苯基]胺基}吡嗪-2-基)胺基]環己烷羧酸(實施例437)(59 mg)的淡黃色粉末。4-[(5-Aminocarbamimido-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]] Addition of 10% sodium hydroxide to a mixture of amino}pyrazin-2-yl)amino]cyclohexanecarboxylate (Example 435) (126 mg), THF (2 mL) and methanol (2 mL) The aqueous solution (1 mL) was heated to reflux for 2 hours. 10% hydrochloric acid was added to the reaction solution to adjust the pH to about 7, and the resulting solid was filtered. The solid was purified by gel column chromatography (dissolved solution; chloroform:methanol) to give 4-[(5-aminocarbazin-3-ethyl-6-{[4- (4-Methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylic acid (Example 436) (47 mg Light yellowish white powder, and highly polar product 4-[(5-aminomethylmercapto-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3) - (Trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylic acid (Example 437) (59 mg) as a pale yellow powder.

實施例438Example 438

於4-[(5-胺基甲醯基-3-乙基-6-{[4-(4-甲基哌嗪-1-基)-3-(三氟甲基)苯基]胺基}吡嗪-2-基)胺基]環己烷羧酸(實施例436)(62 mg)、o-胺基苯甲醚(42 mg)及DMF(2 mL)的混合物中，加入1-羥基-1H-苯並三唑一水合物(46 mg)與1-乙基-3-(3-二甲胺丙基)碳化二亞胺鹽酸鹽(65 mg)，在室溫下進行7小時攪拌。將反應液注入於飽和碳酸氫鈉水溶液，以乙酸乙酯萃取。將有機層以水、飽和食鹽水之順次洗淨後，以無水硫酸鈉乾燥，將溶劑經減壓餾去。將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇)進行純化後得到6-乙基-5-({4-[(2-甲氧基苯基)胺基甲醯基]環己基}胺基)-3-{[4-(4-甲基哌嗪-1-基)-3-(三氟甲基)苯基]胺基}吡嗪-2-甲醯胺(33 mg)之黃色粉末。4-[(5-Aminocarbamimid-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino) Add a mixture of pyrazin-2-yl)amino]cyclohexanecarboxylic acid (Example 436) (62 mg), o-aminoanisole (42 mg) and DMF (2 mL) Hydroxy-1H-benzotriazole monohydrate (46 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (65 mg), at room temperature 7 Stir for hours. The reaction solution was poured into a saturated aqueous The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (solvent; chloroform:methanol) to give 6-ethyl-5-({4-[(2-methoxyphenyl)aminomethylmethyl]cyclohexyl }amino)-3-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazine-2-carboxamide (33 mg) Yellow powder.

實施例495Example 495

將6-氯-3-{[3-(1,4-二噁-8-吖螺[4.5]癸-8-基)-4-甲氧基苯基]胺基}-5-[(反式-4-羥基環己基)胺基]吡嗪-2-甲醯胺(實施例482)(0.80 g)、乙酸(4 mL)與水(4 mL)的混合物，在80℃進行3小時攪拌。於反應液加入濃鹽酸(1 mL)，進一步在80℃進行2小時攪拌。冷卻反應液，經減壓濃縮後加入氯仿，以飽和碳酸氫鈉水溶液洗淨。將有機層以無水硫酸鎂乾燥後，將溶劑餾去，以矽膠管柱層析法(溶離液；氯仿：甲醇=10：1-30：1)進行純化後得到6-氯-5-[(反式-4-羥基環己基)胺基]-3-{[4-甲氧基-3-(4-側氧基哌啶-1-基)苯基]胺基}吡嗪-2-甲醯胺(0.74 g)之黃色非晶質。6-Chloro-3-{[3-(1,4-dioxa-8-indole[4.5]癸-8-yl)-4-methoxyphenyl]amino}-5-[(reverse) Mixture of 4-hydroxycyclohexyl)aminopyrazine-2-carboxamide (Example 482) (0.80 g), acetic acid (4 mL) and water (4 mL), stirring at 80 ° C for 3 hours . Concentrated hydrochloric acid (1 mL) was added to the reaction mixture, and the mixture was further stirred at 80 ° C for 2 hours. The reaction solution was cooled, concentrated under reduced pressure, and then filtered and evaporated. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and purified by silica gel column chromatography (solvent; chloroform:methanol = 10:1 to 30:1) to give 6-chloro-5-[( Trans-4-hydroxycyclohexyl)amino]-3-{[4-methoxy-3-(4-oxopiperidin-1-yl)phenyl]amino}pyrazine-2-yl Indoleamine (0.74 g) is yellow amorphous.

實施例499Example 499

於6-氯-5-[(反式-4-羥基環己基)胺基]-3-{[4-甲氧基-3-(4-側氧基哌啶-1-基)苯基]胺基}吡嗪-2-甲醯胺(實施例495)(0.346 mg)、N-甲基哌嗪(0.12 mL)及1,2-二氯乙烷(10 mL)的混合物中，加入三乙酸基氫化硼鈉(225 mg)，在室溫下進行5小時攪拌。於反應液加入飽和碳酸氫鈉水溶液後，以氯仿萃取，將有機層以飽和食鹽水洗淨。以無水硫酸鈉乾燥後，將溶劑減壓餾去，將殘渣於矽膠管柱層析法(溶離液；氯仿：甲醇：飽和氨水=100：0：0-20：1：0.1)進行純化後得到粗純化物。將所得之粗純化物以乙酸乙酯-二異丙醚固體化後，以乙酸乙酯洗淨後得到6-氯-5-[(反式-4-羥基環己基)胺基]-3-({4-甲氧基-3-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺(39 mg)之淡黃色固體。6-Chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-methoxy-3-(4-oxopiperidin-1-yl)phenyl] a mixture of amino}pyrazine-2-carboxamide (Example 495) (0.346 mg), N-methylpiperazine (0.12 mL) and 1,2-dichloroethane (10 mL) Sodium borohydride acetate (225 mg) was stirred at room temperature for 5 hours. After adding a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture, the mixture was extracted with chloroform, and the organic layer was washed with brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; chloroform: methanol: saturated aqueous ammonia = 100:0:0-20:1:0.1). Crude purified material. The obtained crude product was solidified with ethyl acetate-diisopropyl ether and washed with ethyl acetate to give 6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3- ({4-Methoxy-3-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (39 mg) Light yellow solid.

實施例508Example 508

將6-溴-5-[(反式-4-羥基環己基)胺基]-3-{[3-(甲基磺醯基)苯基]胺基}吡嗪-2-甲醯胺(實施例181)(50 mg)、環丙基硼酸(18 mg)、肆三苯基膦鈀(24 mg)、碳酸鉀(71 mg)、二噁烷(2.5 mL)及水(0.5 mL)的混合物在115℃進行一夜攪拌。將反應液冷卻後，以氯仿、飽和碳酸氫鈉水溶液、飽和食鹽水進行分液操作。將有機層經乾燥後濃縮，將所得之殘渣以矽膠管柱層析法(溶離液；氯仿：甲醇：飽和氨水=100：0：0-10：1：0.1)進行純化。將所得之殘渣以乙酸乙酯-己烷固體化後得到6-環丙基-5-[(反式-4-羥基環己基)胺基]-3-{[3-(甲基磺醯基)苯基]胺基}吡嗪-2-甲醯胺(10 mg)之黃色固體。6-Bromo-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide ( Example 181) (50 mg), cyclopropylboronic acid (18 mg), triphenylphosphine palladium (24 mg), potassium carbonate (71 mg), dioxane (2.5 mL) and water (0.5 mL) The mixture was stirred overnight at 115 °C. After cooling the reaction liquid, the liquid separation operation was carried out with chloroform, a saturated aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried and concentrated, and the obtained residue was purified by silica gel column chromatography (solvent; chloroform: methanol: saturated aqueous ammonia = 100:0:0-10:1:0.1). The residue obtained was solidified with ethyl acetate-hexane to give 6-cyclopropyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl) Phenyl]amino}pyrazine-2-carboxamide (10 mg) as a yellow solid.

實施例534Example 534

於5-[(1-苯甲基哌啶-4-基)胺基]-6-乙基-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)吡嗪-2-甲醯胺(實施例507)(1.31 g)、乙醇(26 mL)與乙酸(13 mL)的混合物中加入氫氧化鈀(0.65 g)，氫氣環境下，在室溫下進行3天攪拌。將觸媒過濾去除後，濃縮溶劑，以氯仿、飽和碳酸氫鈉水溶液進行分液操作。將有機層經濃縮後得到6-乙基-3-({3-甲基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}胺基)-5-(哌啶-4-基胺基)吡嗪-2-甲醯胺(0.73 g)之淡黃色固體。5-[(1-Benzylpiperidin-4-yl)amino]-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-) Addition of hydrazine to a mixture of phenyl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (Example 507) (1.31 g), ethanol (26 mL) and acetic acid (13 mL) Palladium (0.65 g) was stirred at room temperature for 3 days under a hydrogen atmosphere. After the catalyst was removed by filtration, the solvent was concentrated, and a liquid separation operation was carried out using chloroform and a saturated aqueous sodium hydrogencarbonate solution. The organic layer was concentrated to give 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amine -5-(piperidin-4-ylamino)pyrazine-2-carboxamide (0.73 g) as a pale yellow solid.

藉由上述實施例所製造之實施例化合物、及與上述實施例之相同方法，使用各對應原料所製造之實施例化合物的化學結構如表85～表164所示。又，這些實施例化合物之製造方法及物理化學的數據如表165～表183所示。The chemical structures of the example compounds produced by using the respective starting materials by the example compounds produced in the above examples and the same methods as those of the above examples are shown in Tables 85 to 164. Further, the methods for producing the compounds of the examples and the physicochemical data are shown in Tables 165 to 183.

以下，表184～表201表示本發明的其他化合物之結構。這些可藉由上述製造方法或實施例記載方法、及斯業者熟悉的方法、或這些經改變的方法而合成或進行合成。Hereinafter, Tables 184 to 201 show the structures of other compounds of the present invention. These can be synthesized or synthesized by the methods described in the above production methods or examples, methods familiar to those skilled in the art, or modified methods.

且，表中的符號表示以下的意思。Moreover, the symbols in the table indicate the following meanings.

No：化合物號碼、-R11 及-R12 ：一般式中的取代基、cBu：環丁基、2Py：2-吡啶、3Py：3-吡啶、4Py：4-吡啶。No: compound number, -R 11 and -R 12 : a substituent in the general formula, cBu: cyclobutyl, 2Py: 2-pyridine, 3Py: 3-pyridine, 4Py: 4-pyridine.

產業上可利用性Industrial availability

式(I)的化合物或其鹽具有EML4-ALK融合蛋白質之激酶活性的阻斷活性、以及EML4-ALK融合蛋白質依賴性細胞的增殖抑制活性，可作為癌之型態的肺癌、作為其他型態之非小細胞肺癌或小細胞肺癌、又作為其他型態之ALK融合聚核苷酸陽性的癌、進一步作為其他型態之ALK融合聚核苷酸陽性的肺癌、進一步作為其他型態之ALK融合聚核苷酸陽性的非小細胞肺癌、進一步作為其他型態之ALK融合蛋白質陽性的癌、進一步作為其他型態之ALK融合蛋白質陽性的肺癌、進一步作為其他型態之ALK融合蛋白質陽性的非小細胞肺癌、進一步作為其他型態之EML4-ALK融合聚核苷酸陽性的癌、進一步作為其他型態之EML4-ALK融合聚核苷酸陽性的肺癌、進一步作為其他型態之EML4-ALK融合聚核苷酸陽性的非小細胞肺癌、進一步作為其他型態之EML4-ALK融合蛋白質陽性的癌、進一步作為其他型態之EML4-ALK融合蛋白質陽性的肺癌、進一步作為其他型態之EML4-ALK融合蛋白質陽性的非小細胞肺癌等預防及/或治療用醫藥組成物的有效成分而使用。The compound of the formula (I) or a salt thereof has a blocking activity of the kinase activity of the EML4-ALK fusion protein, and a proliferation inhibitory activity of the EML4-ALK fusion protein-dependent cell, and can be used as a cancer type lung cancer, as another type Non-small cell lung cancer or small cell lung cancer, as another type of ALK fusion polynucleotide-positive cancer, further as another type of ALK fusion polynucleotide-positive lung cancer, further as another type of ALK fusion Polynucleotide-positive non-small cell lung cancer, cancer further positive for other types of ALK fusion protein, lung cancer further positive for other types of ALK fusion protein, further non-small as positive for other types of ALK fusion protein Cell lung cancer, further as another type of EML4-ALK fusion polynucleotide-positive cancer, further as another type of EML4-ALK fusion polynucleotide-positive lung cancer, further as another type of EML4-ALK fusion polymerization Nucleotide-positive non-small cell lung cancer, further as another type of EML4-ALK fusion protein-positive cancer, further as another type of EML4 The ALK fusion protein-positive lung cancer is further used as an active ingredient of a pharmaceutical composition for prevention and/or treatment such as non-small cell lung cancer positive for other types of EML4-ALK fusion protein.

Claims (9)

一種化合物或其鹽，其為6-乙基-5-〔(反式-4-羥基環己基)胺基〕-3-{〔4-(4-甲基哌嗪-1-基)苯基〕胺基}吡嗪-2-甲醯胺、6-乙基-5-〔(反式-4-羥基環己基)胺基〕-3-({4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕苯基}胺基)吡嗪-2-甲醯胺、5-〔(反式-4-羥基環己基)胺基〕-6-異丙基-3-{〔4-(4-甲基哌嗪-1-基)苯基〕胺基}吡嗪-2-甲醯胺、6-乙基-5-〔(反式-4-羥基環己基)胺基〕-3-({4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕-3-(三氟甲基)苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-〔(反式-4-羥基環己基)胺基〕-3-({3-甲基-4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕苯基}胺基)吡嗪-2-甲醯胺、5-〔(反式-4-羥基環己基)胺基〕-6-異丙基-3-({4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕-3-(三氟甲基)苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-〔(順式-4-羥基-4-甲基環己基)胺基〕-3-({3-甲基-4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕苯基}胺基)吡嗪-2-甲醯胺、6-乙基-5-〔(反式-4-羥基環己基)胺基〕-3-{〔4-(4-異丙基哌嗪-1-基)-3-甲基苯基〕胺基}吡嗪-2-甲醯 胺、6-乙基-5-〔(反式-4-羥基-4-甲基環己基)胺基〕-3-({3-甲基-4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕苯基}胺基)吡嗪-2-甲醯胺、6-乙基-3-({3-甲基-4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、6-氯-5-〔(反式-4-羥基環己基)胺基〕-3-({3-甲基-4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕苯基}胺基)吡嗪-2-甲醯胺、6-乙基-3-({4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、6-乙基-3-({3-甲氧基-4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、6-異丙基-3-({4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、6-乙基-3-{〔3-氟-4-(4-甲基哌嗪-1-基)苯基〕胺基}-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、6-異丙基-3-{〔3-甲氧基-4-(4-甲基哌嗪-1-基)苯基〕胺基}-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、 6-異丙基-3-{〔4-(4-甲基哌嗪-1-基)苯基〕胺基}-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺、或6-乙基-3-({3-甲基-4-〔4-(1-甲基哌啶-4-基)哌嗪-1-基〕苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺。 A compound or a salt thereof, which is 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)phenyl Amino}pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylperidine) Pyrazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl -3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxy ring) Hexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyridinium Pyrazine-2-carboxamide, 6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylperidine) Pyrazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl -3-({4-[4-(4-Methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-yl Indoleamine, 6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methyl) Pyrazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 6 -ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpiperazin-1-yl)-3-methylphenyl]amine }pyrazine-2-carboxamidine Amine, 6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazine) -1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide, 6-ethyl-3-({3-methyl-4-[4-(4-) Piperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6- Chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1- Phenyl)amino)pyrazine-2-carboxamide, 6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl] Phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-ethyl-3-({3-methoxy-4- [4-(4-Methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2 -Procarbamide, 6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(four Hydrogen-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-ethyl-3-{[3-fluoro-4-(4-methylpiperazin-1-yl)benzene Amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide, 6-isopropyl-3-{[3-methoxy-4- (4-methylpiperazin-1-yl)phenyl] Yl} -5- (tetrahydro -2H- pyran-4-ylamino) pyrazine-2-Amides, 6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine 2-carbamamine, or 6-ethyl-3-({3-methyl-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}amine 5-(4-hydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide. 如請求項1之化合物或其鹽，其為5-〔(反式-4-羥基環己基)胺基〕-6-異丙基-3-({4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕-3-(三氟甲基)苯基}胺基)吡嗪-2-甲醯胺。 The compound of claim 1 or a salt thereof, which is 5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperidin) Pyrazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide. 如請求項1之化合物或其鹽，其為6-乙基-5-〔(順式-4-羥基-4-甲基環己基)胺基〕-3-({3-甲基-4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕苯基}胺基)吡嗪-2-甲醯胺。 The compound of claim 1 or a salt thereof, which is 6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4- [4-(4-Methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide. 如請求項1之化合物或其鹽，其為6-乙基-3-({3-甲氧基-4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺。 The compound of claim 1, or a salt thereof, which is 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl) Phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide. 如請求項1之化合物或其鹽，其為6-異丙基-3-({4-〔4-(4-甲基哌嗪-1-基)哌啶-1-基〕苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺。 The compound of claim 1, or a salt thereof, which is 6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amine 5-(4-hydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide. 如請求項1之化合物或其鹽，其為6-乙基-3-({3-甲基-4-〔4-(1-甲基哌啶-4-基)哌嗪-1-基〕苯基}胺基)-5-(四氫-2H-吡喃-4-基胺基)吡嗪-2-甲醯胺。 The compound of claim 1, or a salt thereof, which is 6-ethyl-3-({3-methyl-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl] Phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide. 一種醫藥組成物，其特徵為含有如申請專利範圍第1項之化合物或其鹽、及製藥學上可被接受的賦形劑。 A pharmaceutical composition comprising a compound as claimed in claim 1 or a salt thereof, and a pharmaceutically acceptable excipient. 一種EML4-ALK融合蛋白質的激酶活性之阻斷劑，其特徵為含有如申請專利範圍第1項之化合物或其鹽。 A blocker for kinase activity of an EML4-ALK fusion protein, which comprises a compound according to claim 1 or a salt thereof. 一種非小細胞肺癌或急性骨髓性白血病的治療用醫藥組成物，其特徵為含有如申請專利範圍第1項之化合物或其鹽。 A therapeutic pharmaceutical composition for non-small cell lung cancer or acute myeloid leukemia, which comprises the compound of the first aspect of the patent application or a salt thereof.
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